Gene Therapy Clinical Research

Investigators at the Center for Gene Therapy in The Research Institute at Nationwide Children's Hospital are currently conducting numerous clinical research studies, described in detail below. The Neurosciences Center at Nationwide Children's offers patients and families a comprehensive approach to the care for children and adolescents with disorders of the brain, spine and nervous system; from initial diagnosis and treatment to rehabilitation and long-term follow-up care.

Learn more about the SMA type 1 clinical trial. Please note: this trial is not recruiting participants at this time. Information for parents of children with SMA1 who want to learn more about study participation can visit: studysmanow.com.

Gene Therapy

Batten CLN6 Gene Therapy (Open Label, Phase I/ II)

Principal Investigator: Jerry R Mendell, MD

Sponsor: Gray Foundation

Enrollment Status: Recruiting

Time Commitment: 2 years

Background: Batten Disease, also termed as Neuronal Ceroid Lipofuscinosis (NCLs) are fatal neurodegenerative, lysosomal storage disorders of the nervous system. Historically, NCLs are classified as Infantile, Late-infantile, Juvenile, Adult, and Northern Epilepsy types. NCLs are inherited in an autosomal recessive manner with the exception of adult onset, which can be an autosomal dominant manner. Presently, in the era of evolving medicine, NCLs are classified based on phenotypes and their known associated genes. CLN6 gene is associated with minor variant of Late-infantile phenotype. Batten CLN6 disease onset is usually between 18 months to 8 years. Cognitive/motor decline, vision loss or decreased visual acuity, and seizures are commonly seen in this particular type. Currently there is no specific treatment available.

Purpose: This is the first clinical gene therapy trial for Batten CLN6 Disease. The CLN6 gene will be delivered using self-complementary adeno-associated virus (scAAV) serotype 9. This vector is not yet approved by FDA. We are conducting this study to evaluate the safety of gene transfer by this vector.

Inclusion Criteria:

  1. Diagnosis of CLN6 disease determined by genotype available at Screening
  2. Quantitative clinical assessment of the Hamburg motor-language aggregate score at Screening on CLN2 disease motor-language scale, as defined in the Ratings Assessment Guideline.
  3. Age ≥1 year
  4. Written informed consent from parent or legal guardian and assent from subject, if appropriate.
  5. Ability to comply with protocol required assessments (laboratory sample collection, EEG, ECG, MRI, etc.

Exclusion Criteria:

  1. Another inherited neurologic disease, e.g., other forms of CLN or seizures unrelated to CLN2 disease (patients with febrile seizures may be eligible)
  2. Another neurological illness that may have caused cognitive decline (e.g., trauma, meningitis, hemorrhage) before screening
  3. Active viral infection
  4. Has received stem cell or bone marrow transplantation for CLN6 disease
  5. Contraindications for spinal tap procedure (e.g., spina bifida, meningitis, impairment, or clotting abnormalities)
  6. Contraindications for MRI scans (e.g., cardiac pacemaker, metal fragment or chip in the eye, aneurysm clip in the brain)
  7. Episode of generalized motor status epilepticus within 4 weeks before the First Dose visit
  8. Severe infection (e.g., pneumonia, pyelonephritis, or meningitis) within 4 weeks before the First Dose visit (enrollment may be postponed)
  9. Has received any investigational medication within 30 days before the first infusion of study drug
  10. Patients with Anti-AAV9 antibody titers ≥ 1:50 as determined by ELISA binding immunoassay.
  11. Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject's ability to comply with the protocol required testing or procedures or compromise the subject's wellbeing, safety, or clinical interpretability
  12. Pregnancy any time during the study; a female subject judged by the investigator to be of childbearing potential will be tested for pregnancy
  13. Abnormal laboratory values considered clinically significant (GGT > 3XULN, Bilirubin ≥ 3.0 mg/dL , Creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/Dl; WBC > 15,000 per cmm)

Contact Information:

Alana Mahley, BS
Clinical Research Coordinator II
Alana.Mahley@nationwidechildrens.org
(614) 355-2606

Learn More at ClinicalTrials.gov

Phase I/IIa Gene Transfer Clinical Trial for Juvenile Neuronal Ceroid Lipofuscinosis, Delivering the CLN3 Gene by Self-Complementary AAV9

Sponsor: Amicus

Principal Investigator: Emily De Los Reyes, MD

Enrollment Status: Not Yet Recruiting

Time Commitment: 12-13 visits over a three year period. This includes 1-2 visits for pre-screening and 11-12 visits for treatment and active follow-up.

Background: Juvenile NCL or Batten’s disease is a severe neurodegenerative disorder leading to blindness, motor impairment, dementia, and epilepsy. Mutations or changes in the CLN3 gene can cause Batten’s disease by not allowing our bodies to make enough of the CLN3 protein called battenin. Without enough battenin, the cells in our central nervous system gradually are damaged and die. One way to treat this disease is to increase the amount of battenin protein in the patients’ cells and improve the functioning of those cells. To do this, doctors will use a treatment called gene therapy to express more CLN3 gene in the central nervous system of patients. A vehicle is used to insert the gene into the cells in the central nervous system. This vehicle called adeno associated virus.

Purpose: This study will test a new drug that hopes to deliver the CLN3 gene into patients’ nervous systems and increase the amount of battenin protein in their cells. The CLN3 gene will be introduced into a patient’s body using a virus called adeno-associated virus 9 (AAV9). This trial will evaluate safety and effectiveness of AAV9 delivered gene therapy for juvenile Batten disease caused by CLN3 mutations. This is the first intrathecal gene therapy clinical trial for juvenile Batten’s Disease caused by mutations in the CLN3 gene.

Inclusion Criteria:

  1. Diagnosis of CLN3 disease determined by genotype available at screening
  2. Age ≥3 years through 10 years of age
  3. UBDRS physical impairment score of ≤7
  4. Patients must be able to walk independently at least 50 feet

Exclusion Criteria:

  1. Presence of another inherited neurologic or metabolic disease, e.g., other forms of CLN or seizures unrelated to CLN3 disease (patients with febrile seizures may be eligible at discretion of the Investigator)
  2. Presence of another neurological illness that may have caused cognitive decline (e.g., trauma, meningitis, hemorrhage) before screening
  3. Active viral infection (includes HIV or serology positive for hepatitis B or C)
  4. Patients with two consecutive abnormal aminotransaminase liver tests (>3 times the upper limit of normal) at screening
  5. Patients with Anti-AAV9 antibody titers >1:400 as determined by ELISA binding immunoassay
  6. Abnormal laboratory values considered clinically significant (See Table 4)
  7. Presence of immunologic disease
  8. Has received stem cell or bone marrow transplantation
  9. Received any form of organ transplant
  10. History of or current chemotherapy, radiotherapy or other immunosuppression therapy within the past 30 days (corticosteroid treatment may be permitted at the discretion of the PI)
  11. Contraindications for intrathecal injection procedure (e.g. spina bifida, meningitis, impairment, or clotting abnormalities)
  12. Contraindications for MRI scans (e.g., cardiac pacemaker, metal fragment or chip in the eye, aneurysm clip in the brain)
  13. Poorly controlled seizures – intractable epilepsy
  14. Episode of generalized motor status epilepticus within four weeks before the First Dose visit
  15. History of corneal or intraocular surgery
  16. Severe infection (e.g., upper respiratory tract infection, pneumonia, pyelonephritis, or meningitis) within four weeks before the First Dose visit (enrollment may be postponed)
  17. Has received any investigational medication within 30 days before the first infusion of study drug
  18. Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject’s ability to comply with the protocol required testing or procedures or compromise the subject’s wellbeing, safety, or clinical interpretability
  19. Pregnancy any time during the study; a female subject judged by the investigator to be of childbearing potential will be tested for pregnancy
  20. Family does not want to disclose patient's study participation with primary care physician and other medical providers
  21. Those with bleeding disorders or any other medical conditions or circumstances in which intrathecal (IT) administration of the product or lumbar puncture (for collection of CSF)

Contact Information:

Clinical Research Service
(614) 722-2650
CRSHelps@nationwidechildrens.org
Phase I/IIa Gene Therapy Trial for Treatment of Charcot-Marie-Tooth Neuropathy Type 1A

Principal Investigator: Zarife Sahenk, MD, PhD

Sponsor: NIH, National Institute of Neurological Disorders and Stroke (NINDS)

Enrollment Status: Not Recruiting

Time Commitment: 2 years

Background: Charcot-Marie-Tooth (CMT) hereditary neuropathy is a group of disorders characterized by a chronic motor and sensory polyneuropathy, also known as hereditary motor and sensory neuropathy (HMSN). These disorders are caused by gene mutations whose protein products are expressed in myelin and/or axons of peripheral nerves. Different mutations within the same gene, which express various clinical phenotypes is a common finding in this group of neuropathies. The most common initial presentation of CMT is distal weakness and atrophy. Hence patients present with foot drop and pes cavus. Sensory symptoms are often present but tend to be less prominent. Later in the course, foot deformities such as hammertoes ensue, along with hand weakness and atrophy becomes a challenges in treating CMT.

Traditionally, CMT classification was based on peripheral neuropathy (determined by nerve conduction velocity) and mode of inheritance. For example, CMT1, CMT2, DI-CMT (Dominant Intermediate). But recent evolving genetics has pushed for new CMT naming system based on gene involvement, which already been proposed.

CMT1A, most common form of CMT is associated with a 1.5 Mb duplication or, less commonly, a point mutation of the peripheral myelin protein 22 (PMP22) gene on chromosome 17p11.2-p1; duplication causes overexpression of PMP22, on the other hand, point mutations alter distribution of the protein. Patients with point mutations have has more prominent symptoms. Patients with CMT1A may have associated with sleep apnea. Ddiabetes mellitus, vitamin deficiencies, and immune-mediated neuropathies may further exacerbate CMT condition.

Currently there is no treatment for this condition.  Ascorbic acid supplements have been highly touted to help, but multiple studies have shown no benefit. A human trial of NT-3 provided by Regeneron showed clinical efficacy after 24 weeks of treatment accompanied by increased numbers of myelinated nerve fibers in post-treatment sural nerve biopsies.

Purpose: To evaluate the safety of administering neurotrophin-3 (NT-3) encoding NTF3 gene using self-complementary adeno-associated virus (scAAV) type. The safety of dose escalation will also be evaluated over the course of the study.

Inclusion Criteria:

  1. Subjects 15- 35 years old inclusive with CMT1A will be enrolled (Cohort 1 will only include subjects that are 18 to 35 years of age)
  2. All must exhibit a 1.5 Mb duplication at 17p11.2 inclusive of the peripheral myelin protein 22 (PMP22) gene
  3. Males and females of any ethnic or racial group
  4. Patients must exhibit weakness of the ankle dorsiflexion muscle (but have full range of motion (ROM) against gravity and able stand on heels for 3 seconds or greater)
  5. Abnormal nerve conduction velocities
  6. Ability to cooperate for clinical evaluation and repeat nerve conduction studies
  7. Willingness of sexually active subjects to practice a reliable method of contraception during the study

Exclusion Criteria:

  1. Active viral infection based on clinical observations or serological evidence of HIV, or Hepatitis B or C infection
  2. Ongoing immunosuppressive therapy or immunosuppressive therapy within 6 months of starting the trial (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin)
  3. Persistent leukopenia or leukocytosis (WBC ≤ 3.5 K/µL or ≥ 20.0 K/µL) or an absolute neutrophil count < 1.5K/µL
  4. Subjects with AAV1 binding antibody titers ≥ 1:50 as determined by ELISA immunoassay
  5. Subjects with circulating anti-NT-3 titers ≥ 1:50 as determined by ELISA immunoassay
  6. Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
  7. Treatment with any investigational medication within 30 days before the infusion of study drug
  8. Abnormal laboratory values considered clinically significant (GGT > 3XULN, bilirubin ≥ 3.0 mg/dL, creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/Dl; WBC > 15,000 per cmm)
  9. Ankle contractures or surgeries preventing proper muscle strength testing
  10. Pregnancy or lactation (female subjects will be tested for pregnancy)
  11. Limb surgery in the past six months
  12. Any medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject’s ability to comply with the protocol required testing or procedures or compromise the subject’s wellbeing, safety, or clinical interpretability
  13. Severe infection (e.g. pneumonia, pyelonephritis, or meningitis) within 4 weeks before gene transfer visit (enrollment may be postponed)
  14. Any subject unwilling to disclose patient's study participation with primary care physician and other medical providers
Intravenous Gene Transfer for Duchenne Muscular Dystrophy Using Adeno Associated Virus

Principal Investigator: Jerry R Mendell, MD

Sponsor: Washington University School of Medicine

Enrollment Status: Recruiting

Time Commitment: 3 years

Background: Dystrophinopathies are named after diseases that are caused by mutations of the dystrophin gene which is located on the X chromosome. Duchenne muscular dystrophy (DMD) is associated with the most severe clinical symptoms among all. Histologic and laboratory evidence of a myopathy may be observed from birth, but clinical onset occurs between two and three years of age. Proximal muscle weakness before the distal, and the lower before the upper extremities are present almost every patient with DMD. The affected child therefore has difficulty running, jumping, and walking up steps. When arising from the floor, affected boys may also use hand support to push themselves to an upright position, an action termed Gower's sign. An unusual waddling gait, lumbar lordosis, and calf enlargement are usually observed. Leg pain and cramps are common complain among DMD patients. Other motor signs and symptoms that may be present include toe walking, decreased endurance, decreased head control when pulled to sit, flat feet, frequent falls, clumsiness, gross motor delay, inability to keep up with peers, and loss of motor skills.

Other associated problems with DMD are elevated creatinine kinase (CK) and transaminases, growth delay, cardiomyopathy, orthopedic complications, and cognitive and behavioral disorders. Most patients become wheelchair bound by the age of twelve and die in their late teens or twenties from respiratory insufficiency or cardiomyopathy; only a few DMD patients survive beyond the third decade.

Two most common form of genetic impairments in Duchenne are deletions/ duplication, and point mutation. Currently available mainstay of pharmacologic treatment for DMD is Glucocorticoids.

Purpose: This study will try to find out if it is safe to deliver microdystrophin gene through the blood stream.

Inclusion Criteria:

  1. Age of enrollment: Cohort A (n=6) is between 3 months to 3 years of age, inclusive; Cohort B (n=6) is between 4 to7 years of age, inclusive. 
  2. Molecular characterization of the DMD gene with frameshift (deletion or duplication), or premature stop codon mutation between exons 18 to 58.   
  3. Indication of symptomatic muscular dystrophy
    • CK elevation >1000 U/L and
    • Cohort A: below average on the Bayley-III motor assessment for gross motor defined as a scaled score of ≤9. Any subject that is 43-47 months of age, inclusive, at time of screening will have the scaled score calculated compared to normative data for 42 month old children. The Bayley-III provides normative data for children 1-42 months of age.
    • Cohort B: below average on the 100 Meter Timed Test defined as ≤ 80% predicted1.
  4. Males of any ethnic group will be eligible.
  5. Ability to cooperate with motor assessment testing.
  6. For Cohort A subjects: No previous treatment with corticosteroids. For Cohort B subjects: Stable dose equivalent of oral corticosteroids for at least 12 weeks prior to screening and the dose is expected to remain constant (except for potential modifications to accommodate changes in weight) throughout the study.

Exclusion Criteria:

  1. Active viral infection based on clinical observations.
  2. Signs of cardiomyopathy, including echocardiogram with ejection fraction below 40%.
  3. Serological evidence of HIV infection, or Hepatitis B or C infection.
  4. Diagnosis of (or ongoing treatment for) an autoimmune disease.
  5. Abnormal laboratory values considered clinically significant (GGT > 3XULN, bilirubin ≥ 3.0 mg/dL, creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/Dl; WBC > 18,500 per cmm).
  6. Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer.
  7. Subjects with AAVrh74 or AAV8 antibody titers > 1:400 as determined by ELISA immunoassay.
    • If endpoint titer is positive at screening, testing may be repeated prior to exclusion.
    • If present in infant and mother is positive for same antibody titers, mother will be asked not to breast feed and infant can be enrolled if antibodies drop ≤1:400 within 12 weeks.
  8. Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject’s ability to comply with the protocol required testing or procedures or compromise the subject’s wellbeing, safety, or clinical interpretability.
  9. Severe infection (e.g., pneumonia, pyelonephritis, or meningitis) within 4 weeks before gene transfer visit (enrollment may be postponed).
  10. Has received any investigational medication (other than corticosteroids) or exon skipping medications (including ExonDys 51), experimental or otherwise, in the last 6 months prior to screening for this study.
  11. Has had any type of gene therapy, cell based therapy (e.g. stem cell transplantation), or CRISPR/Cas9.
  12. Family does not want to disclose patient’s study participation with primary care physician and other medical providers.

Contact Information: 

Amanda Nicholl 
Clinical Research Coordinator - RN Gene Therapy
Amanda.Nicholl@NationwideChildrens.org 
(614) 355-2765

Learn More at ClinicalTrials.gov

Phase I/IIa gene transfer clinical trial for Duchenne Muscular Dystrophy using AAVrh74.MCK.GALGT2

Principal Investigator: Kevin Flanigan, MD

Co-Investigator: Megan Waldrop, MD

Enrollment Status: Active, Recruiting

Time Commitment: 12 visits at Nationwide Children’s Hospital over 2 years plus 3 additional local visits for blood draws. .Additionally, there is 5 years of long-term follow up with no on site time commitment.

Background: Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy. A non-working gene that results in the failure to make a properly functioning protein called dystrophin causes DMD. Dystrophin protects the integrity of muscles, however, there are other genes present in our genome that can also serve the same function in muscle and can substitute (or be a surrogate) for dystrophin. One of these genes, called GALGT2 is a promising surrogate to treat DMD because it has been shown to improve muscle function and strength in animal models with muscular dystrophy. Also it is a naturally occurring protein that DMD patients encounter in their body and because of this, there is lower risk of a patient developing an immune response to the new protein.

Purpose: This study is designed to test the safety of delivering a dystrophin substitute (or “surrogate”) gene called GALGT2 to functionally take the place of the non-working dystrophin gene. Doctors will use a method called “gene transfer” to express more GALGT2 than normal in the patient’s leg muscles. The GALGT2 gene is transported into muscle using a vehicle. The vehicle is a harmless virus called adeno-associated virus (AAV). The Study Doctor is investigating the safety of this drug thought to help make GALGT2 which may be very helpful in protecting the muscle tissue in people with DMD.

Inclusion Criteria:

  1. Patients able to walk of age 4 years or older
  2. Confirmed mutations in the DMD gene using a clinically accepted technique that completely defines the mutation
  3. Measurably impaired muscle function (defined as less than 80% of the predicted value for age on 100 MWT), but with sufficient muscle preservation to ensure assessment of muscle transfection based on clinical evaluation by the PI and expert colleagues. This degree of preservation will include:
    • Ability to extend the knee fully against gravity
    • Preserved ambulation with ability to walk ≥ 350 meters during the 6MWT.
    • A magnetic resonance image (MRI) of the quadriceps showing preservation of sufficient muscle mass to permit transfection.
  4. Males of any ethnic or racial group will be eligible.
  5. Ability to cooperate with muscle testing
  6. Stable dose of corticosteroid therapy (including prednisone, prednisolone, or deflazacort and their generic forms) for at least 12 weeks prior to gene transfer.

Exclusion Criteria:

  1. Active viral infection based on clinical observations.
  2. The presence of a DMD mutation without weakness or loss of function
  3. Subject is amenable to or is currently being treated with eteplirsen.
  4. Symptoms or signs of cardiomyopathy, including:
    • Dyspnea on exertion, pedal edema, shortness of breath upon lying flat, or rales at the base of the lungs
    • Echocardiogram with ejection fraction below 40%
  5. Serological evidence of HIV infection, or Hepatitis B or C infection
  6. Diagnosis of (or ongoing treatment for) an autoimmune disease
  7. Persistent leukopenia or leukocytosis (WBC ≤ 3.5 K/µL or ≥ 20.0 K/µL) or an absolute neutrophil count < 1.5K/µL
  8. Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
  9. AAVrh74 binding antibody titers ≥ 1:50 as determined by ELISA immunoassay
  10. Presence of circulating anti-Sda antibodies as determined by study approved laboratory.
  11. Abnormal laboratory values in the clinically significant range in the Table 1 below, based upon normal values in the Nationwide Children’s Hospital Laboratory.

Contact Information:

Federica Rinaldi, Clinical Research Program Coordinator
Federica.Rinaldi@nationwidechildrens.org
(614) 355-2897

Carlee Giesige, Clinical Research Coordinator
Carlee.Giesige@nationwidechildrens.org
(614) 355-2727

Licensed by Sarepta Therapeutics

Learn More at ClinicalTrials.org

Phase I/IIa Gene Transfer Clinical Trial for LGMD2E Using Adeno Associated Virus (AAV) Administered by Systemic Perfusion

Principal Investigator: Jerry R Mendell, MD

Sponsor: Myonexus Therapeutic

Enrollment Status: Enrolling

Time Commitment: Active follow-up over 3 years, Placebo subjects will be in the study for approximately 1 additional year.

Background: LGMD2E is one of the variants of Limb Girdle Muscular Dystrophies (LGMD). LGMD2E is caused by a non-working β-sarcoglycan gene that results in the body not making a properly functioning protein that is also called beta-sarcoglycan. When β-sarcoglycan protein is absent or changed, the muscle membrane can be damaged. Proteins are the building blocks of all tissues. They are produced by genes that are found in our body. If a gene is not working, it will not make the correct protein or enough of it. This can include proteins needed by muscles which can cause a disease like muscular dystrophy. LGMD2E typically presents with difficulty running, jumping and climbing stairs within the first decade of life. Cardiac involvement is commonly seen in this disease. There is currently no established treatment for LGMD2E.

Purpose: We will evaluate safety and sustainability of efficacy benefits throughout the study after the gene transfer.

Inclusion Criteria:

  1. Subjects ages 4 through age 15, inclusive
  2. Males or females of any ethnic group
  3. SGCB DNA gene mutations at both alleles
  4. Weakness demonstrated based on history of difficulty running, jumping and climbing stairs
  5. 100m timed test: ≥ 40% of predicted for age, height, and weight matched healthy controls at the screening visit
  6. Ability to cooperate with muscle testing
  7. Willingness of sexually active subjects with reproductive capacity to practice reliable method of contraception (if appropriate), during the first six months after gene therapy

Exclusion Criteria:

  1. Active viral infection based on clinical observations
  2. Cardiac MRI determined left ventricular ejection fraction <40%
  3. Serological evidence of HIV infection, or Hepatitis B or C infection
  4. Diagnosis of (or ongoing treatment for) an autoimmune disease
  5. Abnormal laboratory values considered clinically significant (GGT > 3XULN, bilirubin ≥ 3.0 mg/dL, creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/Dl; WBC > 15,000 per cmm), see Table 2 below
  6. Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
  7. Pregnancy
  8. Subjects with AAVrh74 binding antibody titers > 1:400 as determined by ELISA immunoassay. If endpoint titer is positive at screening, testing may be repeated in 1 month.
  9. Has a medical condition or circumstance that could compromise the protocol compliance or compromise safety.
  10. Severe infection (e.g. pneumonia, pyelonephritis, or meningitis) within 4 weeks before gene transfer visit (enrollment may be postponed)
  11. Family does not want to disclose patient’s study participation with primary care physician and other medical providers.

Contact Information: 

Stephanie Diemer, MS
Clinical Research Coordinator II
Stephanie.Diemer@nationwidechildrens.org
(614) 355-2679

Phase I/II Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH for Mucopolysaccharidosis (MPS) IIIA

Principal Investigator: Kevin Flanigan, MD

Co-Investigators: Kim McBride, MD and Kristen Truxal, MD

Sponsor: Abeona Therapeutics, Inc

Enrollment Status: Recruiting by Invitation

Time Commitment: 12 visits at Nationwide Children’s Hospital over 2 years plus 5 additional home visits for blood draws. Additionally, there is 5 years of long-term follow up with no on site time commitment.

Background: MPS IIIA, also called Sanfilippo syndrome type A is a rare genetic condition. This is a progressive disease that affects many systems throughout the body. MPS IIIB is caused by a build-up of a substance called glycosaminoglycans (or GAGs) because an enzyme called SGSH does not work properly. We are investigating the safety of a gene therapy that replaces the faulty enzyme with one that works and hopefully leads to a reduction in GAGs. This gene transfer will use a special virus to deliver the gene to the entire body.

Purpose: This is a study to find out if it is safe to deliver the SGSH viral vector through the blood stream in children with MPS IIIB. It is the first time this vector will be tested in human volunteers.

Inclusion Criteria:

  1. Age 6 months old or greater
  2. Confirmed diagnosis of MPS IIIA by both of the following methods:
    • No detectable or significantly reduced SGSH enzyme activity by plasma, serum, or leukocyte assay
    • Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the SGSH gene
  3. Clinical history or examination features of neurologic dysfunction

Exclusion Criteria:

  1. Inability to participate in the clinical evaluation as determined by the Principal Investigator
  2. Identification of two nonsense or null variants on genetic testing of the SGSH gene, as judged by the principal investigator
  3. Has evidence of an attenuated phenotype of MPS IIIA, as judged by the principal investigator
  4. Presence of a concomitant medical condition that precludes lumbar puncture or use of anesthetics
  5. Inability to be safely sedated in the opinion of the clinical anesthesiologist
  6. Active viral infection based on clinical observations
  7. Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
  8. Subjects with anti-AAV9 antibody titers ≥ 1:100 as determined by ELISA binding immunoassay
  9. Serology consistent with exposure to HIV, or serology consistent with active hepatitis B or C infection
  10. Bleeding disorder or any other medical condition or circumstance in which a lumbar puncture (for collection of CSF) is contraindicated according to local institutional policy
  11. Visual or hearing impairment sufficient to preclude cooperation with neurodevelopmental testing
  12. Uncontrolled seizure disorder, due to the requirement for multiple MRI examinations as part of the study protocol. Subjects who are stable on anticonvulsive medications may be included
  13. Any item (braces, etc.) which would exclude the patient from being able to undergo MRI according to local institutional policy
  14. Any other situation that would exclude the patient from undergoing any other procedure required in this study
  15. Patients with cardiomyopathy or significant congenital heart abnormalities
  16. The presence of significant non-MPS IlIA related CNS impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study
  17. Abnormal laboratory values Grade 2 or higher as defined in CTCAE v4.0 for GGT, total bilirubin, creatinine, hemoglobin, WBC count, platelet count, PT and aPTT
  18. Female participant who is pregnant or demonstrates a positive urine or hCG result at screening assessment (if applicable).

Contact Information:

Krista Kunkler, Clinical Research Coordinator
Krista.Kunkler@nationwidechildrens.org
(614) 722-2238

Learn More at ClinicalTrials.org

Gene Transfer Clinical Trial for Mucopolysaccharidosis (MPS) IIIB (MPS IIIB)

Principal Investigator: Kevin Flanigan, MD

Co-Investigators: Kim McBride, MD and Kristen Truxal, MD

Sponsor: Abeona Therapeutics, Inc

Enrollment Status: Recruiting by invitation

Time Commitment: 12 visits at Nationwide Children’s Hospital over 2 years plus 5 additional home visits for blood draws. Additionally, there is 5 years of long-term follow up with no on site time commitment.

Background: MPS IIIB, also called Sanfilippo syndrome type B, is a rare genetic condition. This is a progressive disease that affects many systems in the body. MPS IIIB is caused by a build-up of a substance called glycosaminoglycans (or GAGs) because an enzyme (NAGLU) does not work properly. We are investigating the safety of a gene therapy that replaces the faulty enzyme with one that works and hopefully leads to a reduction in GAGs. This gene transfer will use a special virus to deliver the gene to the entire body.  

Purpose: This is a study to find out if it is safe to deliver the NAGLU viral vector through the blood stream in children with MPS IIIB. It is the first time this vector will be tested in human volunteers.

Inclusion Criteria:

  1. Age 6 months old or greater
  2. Confirmed diagnosis of MPS IIIB by both of the following methods:
    • No detectable or significantly reduced NAGLU enzyme activity by plasma, serum, or leukocyte assay
    • Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the NAGLU gene
  3. Clinical history or examination features of neurologic dysfunction

Exclusion Criteria:

  1. Inability to participate in the clinical evaluation as determined by the Principal Investigator
  2. Identification of two nonsense or null variants on genetic testing of the NAGLU gene, as judged by the principal investigator
  3. Has evidence of an attenuated phenotype of MPS IIIB, as judged by the principal investigator

  4. Presence of a coexisting medical condition that prohibits lumbar puncture or use of anesthetics
  5. Inability to be safely sedated in the opinion of the clinical anesthesiologist
  6. Active viral infection based on clinical observations
  7. Coexisting illness or requirement for chronic drug treatment that in the opinion of the Principal Investigator creates unnecessary risks for gene transfer
  8. Subjectswho demonstrate preexisting immunity to the virus used to make the gene transfer vector
  9. Blood test results consistent with exposure to HIV, or consistent with active hepatitis B or C infection
  10. Bleeding disorder or any other medical condition or circumstance in which a lumbar puncture (for collection of cerebrospinal fluid) is contraindicated according to local institutional policy
  11. Visual or hearing impairment severe enough to prevent cooperation with neurodevelopmental testing
  12. Uncontrolled seizure disorder, due to the requirement for multiple MRI examinations as part of the study protocol. Subjects who are stable on antiseizure medications may be included
  13. Any item (orthodontic braces, etc.) which would exclude the subject from being able to undergo MRI according to local institutional policy
  14. Any other situation that would exclude the subject from undergoing any other procedure required in this study
  15. Subjects with cardiomyopathy or significant congenital heart defects as determined by the Principal Investigator
  16. The presence of significant non-MPS IlIB related central nervous system impairment or behavioral problems that would confound the scientific interpretation of results of the study
  17. Abnormal laboratory values Grade 2 or higher as defined in CTCAE v4.0 for GGT, total bilirubin, creatinine, hemoglobin, WBC count, platelet count, PT and aPTT
  18. Female participant who is pregnant or demonstrates a positive urine or serum bhCG result at screening assessment (if applicable).

Contact Information:

Federica Rinaldi, Clinical Research Program Coordinator
Federica.Rinaldi@nationwidechildrens.org
(614) 355-2897

Learn More at ClinicalTrials.org

A Global Study of a Single, One-Time Dose of AVXS-101/ SMN gene Delivered to Infants with Genetically Diagnosed and Pre-symptomatic Spinal Muscular Atrophy (SMA) with Multiple Copies of SMN2

Principal Investigator: Jerry R Mendell, MD

Sponsor: AveXis, Inc.

Enrollment Status: Recruiting

Time Commitment: During the outpatient follow-up period (Days 3 to End of Study at 18, 24 or 36 months of age, dependent upon respective SMN2 copy number), patients will return at regularly scheduled intervals for efficacy and safety assessments until the End of Study when the patient reaches 18 months of age (SMN2 = 2), 24 months of age (SMN2 = 3) or 36 months of age (SMN2 = 4).

Background:  SMA is an autosomal recessive, neurogenetic disorder caused by a loss or mutation in the survival motor neuron 1 gene (SMN1) on chromosome 5q13, which leads to reduced SMN protein levels and a selective dysfunction of motor neurons. Therefore, degeneration of the anterior horn cells in the spinal cord occurs. The same pathology is also noticed in the motor nuclei of the lower brainstem, which results in progressive muscle weakness and atrophy.  SMA is the leading cause of infant mortality due to genetic diseases. Disease severity and clinical prognosis depends on the number of copies of survival motor neuron 2 gene (SMN2). In its most common and severe form (Type 1), hypotonia and progressive weakness are recognized in the first few months of life, leading to diagnosis before 6 months of age and early death due to respiratory failure before 2 years of age. motor neuron loss in SMA Type 2 and Type 3 patients is less profound and a greater population of neurons is able to survive. Until now, widely approved treatment for SMA has been mainly supportive and directed at providing nutrition and respiratory assistance as needed, and treating or preventing complications of weakness. Disease-modifying therapy with Nusinersen is approved in the United States and several other regions, which is mainly given to a selected age group (2 years to 12 years). Limited data is available on Nusinersen in treating older children, adult, and patients with advanced disease.

Purpose: To evaluate the efficacy of AVXS-101 (SMN gene delivered by Adeno Associated Virus Serotype 9) through achievement of developmental milestones, motor function, and survival. We will also evaluate the safety of AVXS-101 through adverse events and clinical laboratory parameters.

Inclusion Criteria:

All patients:

  1. Age ≤6 weeks (≤42 days) at time of dose
  2. Ability to tolerate thin liquids as demonstrated through a formal bedside swallowing test.
  3. Compound muscle action potential (CMAP) ≥2 mV at Baseline; centralized review of CMAP data will be conducted
  4. Gestational age of 35 to 42 weeks
  5. Up-to-date on childhood vaccinations. Seasonal vaccinations that include palivizumab prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) infections are also recommended in accordance with the guidance of local health authorities.
  6. Able and willing to follow the Consensus Statement for Standard of Care in Spinal Muscular Atrophy (J Child Neurol.2007;22[29]:1027-1049).
  7. Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply with study procedures and visit schedule
  8. Genetic diagnosis as described below, obtained from an acceptable newborn or pre-natal screening test method

Patients with 2 copies of SMN2 (n ≥15)

  1. Patients with pre-symptomatic SMA Type 1 as determined by the following features:
  2. 2 copies of SMN2

Patients with 3 copies of SMN2 (n ≥12)

  1. Patients with pre-symptomatic SMA Type 2 as determined by the following features:
  2. 3 copies of SMN2

Patients with 4 copies of SMN2 (n≥17)

  1. Patients with pre-symptomatic SMA Type 3 as determined by the following features: • 4 copies of SMN2

Exclusion Criteria:

  1. Weight at screening visit <2 kg
  2. Hypoxemia (oxygen saturation <96% awake or asleep without any supplemental oxygen or respiratory support) at the screening visit or for altitudes >1000 m, oxygen saturation <92% awake or asleep without any supplemental oxygen or respiratory support at the screening visit
  3. Any clinical signs or symptoms at screening or immediately prior to dosing that are, in the opinion of the Investigator, strongly suggestive of SMA (e.g., tongue fasciculation, hypotonia, areflexia)
  4. Tracheostomy or current prophylactic use or requirement of non-invasive ventilatory support at any time and for any duration prior to screening or during the screening period
  5. Patients with signs of aspiration/inability to tolerate non-thickened liquids based on a formal swallowing test performed as part of screening or patients receiving any non-oral feeding method
  6. Clinically significant abnormalities in hematology or clinical chemistry parameters as determined by the investigator or medical monitor
  7. Treatment with an investigational or commercial product, including nusinersen, given for the treatment of SMA. This includes any history of gene therapy, prior antisense oligonucleotide treatment, or cell transplantation.
  8. Patients whose weight-for-age is below the third percentile based on World Health Organization (WHO) Child Growth Standards [25]
  9. Biological mother with active viral infection as determined by screening laboratory samples (includes human immunodeficiency virus [HIV] or positive serology for hepatitis B or C)
    • Biological mothers with clinical suspicion of Zika virus that meet Centers for Disease Control and Prevention (CDC) Zika virus epidemiological criteria including history of residence in or travel to a geographic region with active Zika transmission at the time of travel will be tested for Zika virus RNA; positive results warrant confirmed negative Zika virus ribonucleic acid (RNA) testing in the patient prior to enrollment
  10. Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within 2 weeks prior to screening
  11. Upper or lower respiratory infection requiring medical attention, medical intervention, or increase in supportive care of any manner within 4 weeks prior to dosing
  12. Severe non-pulmonary/respiratory tract infection (e.g., pyelonephritis, or meningitis) within 4 weeks before administration of gene replacement therapy or concomitant illness that, in the opinion of the Investigator or Sponsor medical monitor, creates unnecessary risks for gene replacement therapy such as:
  13. Major renal or hepatic impairment
  14. Known seizure disorder
  15. Diabetes mellitus
  16. Idiopathic hypocalcuria
  17. Symptomatic cardiomyopathy
  18. Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients
  19. Previous, planned or expected major surgical procedure including scoliosis repair surgery/procedure during the study assessment period
  20. Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as adalimumab, immunosuppressive therapy within 4 weeks prior to gene replacement therapy (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IV immunoglobulin, rituximab)
  21. Anti-AAV9 antibody titer >1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay
    • Should a potential patient demonstrate Anti-AAV9 antibody titer >1:50, he or she may receive retesting inside the 30-day screening period and will be eligible to participate if the Anti-AAV9 antibody titer upon retesting is ≤1:50, provided patient is still <6 week of age at the time of dosing
  22. Biological mother involved with the care of the child refuses anti-AAV9 antibody testing prior to dosing
  23. Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or inability to travel for repeat visits
  24. Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential or to refrain from posting confidential study results/observations on social media sites
  25. Parent(s)/legal guardian(s) refuses to sign consent form

Contact Information: 

Beverly Galliers
Clinical Research Coordinator II
Beverly.Galliers@nationwidechildrens.org
(614) 355-3424

Learn More at ClinicalTrials.gov

Phase 3, Open-Label, Single-Arm, Single-Dose Gene Replacement Therapy Clinical Trial for Patients with Spinal Muscular Atrophy Type 1 (SMA 1) with One or Two Survival Motor Neuron 2 (SMN2) Copies Delivering AVXS-101 (SMN gene) by Intravenous Infusion

Principal Investigator: Jerry R Mendell, MD

Sponsor: AveXis, Inc.

Enrollment Status: Recruiting

Time Commitment: Until 18 months of age

Background:  SMA is an autosomal recessive, neurogenetic disorder caused by a loss or mutation in the survival motor neuron 1 gene (SMN1) on chromosome 5q13, which leads to reduced SMN protein levels and a selective dysfunction of motor neurons. Therefore, degeneration of the anterior horn cells in the spinal cord occurs. The same pathology is also noticed in the motor nuclei of the lower brainstem, which results in progressive muscle weakness and atrophy.  SMA is the leading cause of infant mortality due to genetic diseases. Disease severity and clinical prognosis depends on the number of copies of survival motor neuron 2 gene (SMN2). In its most common and severe form (Type 1), hypotonia and progressive weakness are recognized in the first few months of life, leading to diagnosis before 6 months of age and early death due to respiratory failure before 2 years of age. motor neuron loss in SMA Type 2 and Type 3 patients is less profound and a greater population of neurons is able to survive. Until now, widely approved treatment for SMA has been mainly supportive and directed at providing nutrition and respiratory assistance as needed, and treating or preventing complications of weakness. Disease-modifying therapy with Nusinersen is approved in the United States and several other regions, which is mainly given to a selected age group (2 years to 12 years). Limited data is available on Nusinersen in treating older children, adult, and patients with advanced disease.

Purpose: To evaluate efficacy and adverse effects of AVXS- 101.

Inclusion Criteria:

  1. Patients with SMA Type 1 as determined by the following features:
    • Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or point mutations) and 1 or 2 copies of SMN2 (inclusive of the known SMN2 gene modifier mutation (c.859G>C))2.
  2. The first three patients enrolled must meet the criteria for the Intent-To-Treat Population.
  3. Patients must be < 6 months (< 180 days) of age at the time of AVXS-101 infusion
  4. Patients must have a swallowing evaluation test performed prior to administration of gene replacement therapy
  5. Up-to-date on childhood vaccinations. Seasonal vaccinations that include palivizumab prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) infections are also recommended in accordance with American Academy of Pediatrics (26)
  6. Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply with study procedures and visit schedule

Exclusion Criteria:

  1. Previous, planned or expected scoliosis repair surgery/procedure during the study assessment period
  2. Pulse oximetry < 96% saturation at screening while the patient is awake or asleep without any supplemental oxygen or respiratory support, or for altitudes > 1000 m, oxygen saturation < 92% awake or asleep without any supplemental oxygen or respiratory support. Pulse oximetry saturation may decrease to < 96% after screening provided that the saturation does not decrease by ≥ 4 percentage points.
  3. Tracheostomy or current use or requirement of non-invasive ventilatory support averaging ≥ 6 hours daily over the 7 days prior to the screening visit; or ≥ 6 hours/day on average during the screening period or requiring ventilatory support while awake over the 7 days prior to screening or at any point during the screening period prior to dosing
  4. Patients with signs of aspiration/inability to tolerate nonthickened- liquids based on a formal swallowing test performed as part of screening. Patients with a gastrostomy tube who pass the swallowing test will be allowed to enroll in the study
  5. Patients whose weight-for-age is below the third percentile based on World Health Organization (WHO) Child Growth Standards[25]
  6. Active viral infection (includes human immunodeficiency virus [HIV] or positive serology for hepatitis B or C, or Zika virus)
  7. Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within 2 weeks prior to screening
  8. Upper or lower respiratory infection requiring medical attention, medical intervention, or increase in supportive care of any manner within 4 weeks prior to screening
  9. Severe non-pulmonary/respiratory tract infection (e.g., pyelonephritis, or meningitis) within 4 weeks before administration of gene replacement therapy or concomitant illness that, in the opinion of the Principal Investigator, creates unnecessary risks for gene replacement therapy such as:
    • Major renal or hepatic impairment
    • Known seizure disorder
    • Diabetes mellitus
    • Idiopathic hypocalcuria
    • Symptomatic cardiomyopathy
  10. Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients
  11. Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as adalimumab, immunosuppressive therapy within 3 months prior to gene replacement therapy (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IV immunoglobulin, rituximab)
  12. Anti-AAV9 antibody titer > 1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay. Should a potential patient demonstrate Anti-AAV9 antibody titer > 1:50, he or she may receive retesting within 30 days of the screening period and will be eligible to participate if the Anti-AAV9 antibody titer upon retesting is ≤ 1:50
  13. Clinically significant abnormal laboratory values ( gammaglutamyl- transpeptidase [GGT], ALT, and AST > 3 × ULN, bilirubin ≥ 3.0 mg/dL, creatinine ≥ 1.0 mg/dL, hemoglobin [Hgb] < 8 or > 18 g/dL; white blood cell [WBC] > 20,000 per cmm) prior to gene replacement therapy
  14. Participation in recent SMA treatment clinical study (with the exception of observational cohort studies or non-interventional studies) or receipt of an investigational or commercial compound, product, or therapy administered with the intent to treat SMA (e.g., nusinersen, valproic acid) at any time prior to screening for this study. Oral β-agonists must be discontinued at least 30 days before gene therapy dosing. Inhaled albuterol specifically prescribed for the purposes of respiratory (bronchodilator) management is acceptable and not a contraindication at any time prior to screening for this study
  15. Expectation of major surgical procedures during the study assessment period (e.g., spinal surgery or tracheostomy)
  16. Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or inability to travel for repeat visits
  17. Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential or to refrain from posting confidential study results/observations on social media sites
  18. Parent(s)/legal guardian(s) refuses to sign consent form
  19. Gestational age at birth < 35 weeks (245 days)

Contact Information: 

Markus McColly
Clinical Research Coordinator II
Markus.McColly@nationwidechildrens.org
(614) 355-2825

Learn More at ClinicalTrials.org

Phase I, Open-Label, Dose Comparison Study of AVXS-101 for Sitting but Non-ambulatory Patients with Spinal Muscular Atrophy

Principal Investigator: Jerry R Mendell, MD

Sponsor: AveXis, Inc.

Enrollment Status: Recruiting

Time Commitment: 1 year (approximate)

Background: SMA is an autosomal recessive, neurogenetic disorder caused by a loss or mutation in the survival motor neuron 1 gene (SMN1) on chromosome 5q13, which leads to reduced SMN protein levels and a selective dysfunction of motor neurons. Therefore, degeneration of the anterior horn cells in the spinal cord occurs. The same pathology is also noticed in the motor nuclei of the lower brainstem, which results in progressive muscle weakness and atrophy.  SMA is the leading cause of infant mortality due to genetic diseases. Disease severity and clinical prognosis depends on the number of copies of survival motor neuron 2 gene (SMN2). In its most common and severe form (Type 1), hypotonia and progressive weakness are recognized in the first few months of life, leading to diagnosis before 6 months of age and early death due to respiratory failure before 2 years of age. motor neuron loss in SMA Type 2 and Type 3 patients is less profound and a greater population of neurons is able to survive. Until now, widely approved treatment for SMA has been mainly supportive and directed at providing nutrition and respiratory assistance as needed, and treating or preventing complications of weakness. Disease-modifying therapy with Nusinersen is approved in the United States and several other regions, which is mainly given to a selected age group (2 years to 12 years). Limited data is available on Nusinersen in treating older children, adult, and patients with advanced disease.

Purpose:

  • To assess the safety and tolerability of intrathecal (IT) administration of AVXS-101 by the incidence and severity of adverse events (AEs)
  • To determine the optimal dose of AVXS-101 that demonstrates acceptable safety with maximum preliminary efficacy administered by intrathecal injection

Inclusion Criteria:

  1. Patients > 6 months and up to 60 months (1800 days) of age at time of dosing following diagnostic confirmation during screening period by genotype who demonstrate the ability to sit unassisted for 10 or more seconds but cannot stand or walk • Diagnostic confirmation by genotype includes lab documentation of homozygous absence of SMN1 exon 7; with exactly three copies of SMN2
  2.  Negative gene testing for SMN2 gene modifier mutation (c.859G>C)
  3. Onset of clinical signs and symptoms consistent with spinal muscular atrophy (SMA) at < 12 months of age
  4. Able to sit independently and not standing or walking independently. Definition of sitting independently is defined by the World Health Organization Multicentre Growth Reference Study (WHO-MGRS) criteria of being able to sit up unsupported with head erect for at least 10 seconds. Child should not use arms or hands to balance body or support position.
  5. Meet age-appropriate institutional criteria for use of anesthesia and sedation, as determined necessary by the investigator
  6. Be up-to-date on childhood vaccines. Seasonal vaccinations that include palivizumab prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) infections are also recommended in accordance with American Academy of Pediatrics (AAP 2009)
  7. Parent(s)/legal guardian(s) willing and able to complete the informed consent process

Exclusion Criteria:

  1. Current or historical ability to stand or walk independently
  2. Contraindications for spinal tap procedure or administration of intrathecal therapy (e.g., spina bifida, meningitis, impairment, or clotting abnormalities, or obstructive spinal hardware preventing effective access to cerebrospinal fluid (CSF) space) or presence of an implanted shunt for the drainage of CSF or an implanted central venous (CNS) catheter
  3. Severe contractures as determined by designated Physical Therapist(s) at screening that interfere with either the ability to attain/demonstrate functional measures (e.g., standing, walking) or interferes with ability to receive intrathecal (IT) dosing
  4. Severe scoliosis (defined as ≥ 50° curvature of spine) evident on X-ray examination
  5. Previous, planned or expected scoliosis repair surgery/procedure within 1 year of dose administration
  6. Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse oximetry < 95% saturation at screening while the patient is awake, or for high altitudes > 1000 m, oxygen saturation < 92% while the patient is awake
    • Pulse oximetry saturation must not decrease ≥ four (4) percentage points between screening and highest value on day of dosing
  7. Use or requirement of non-invasive ventilatory support for 12 or more hours daily over the two (2) weeks prior to dosing
  8. Medical necessity for a gastric feeding tube, where the majority of feedings are given by non-oral methods (i.e., nasogastric tube or nasojejunal tube) or patients whose weight-for-age falls below the 3rd percentile based on WHO Child Growth Standards (Onis 2006). Placement of a permanent gastrostomy prior to screening is not an exclusion
  9. Active viral infection (includes human immunodeficiency virus (HIV) or serology positive for hepatitis B or C, or Zika virus)
  10. Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within two (2) weeks prior to study entry
  11. Respiratory infection requiring medical attention, medical intervention or increase in supportive care of any manner within four (4) weeks prior to study entry
  12. Severe non-pulmonary/respiratory tract infection (e.g., pyelonephritis, or meningitis) within four (4) weeks before study dosing or concomitant illness that in the opinion of the Principal Investigator (PI) creates unnecessary risks for gene transfer such as:
    • Major renal or hepatic impairment
    • Known seizure disorder
    • Diabetes mellitus
    • Idiopathic hypocalcuria
    • Symptomatic cardiomyopathy
  13. History of bacterial meningitis or brain or spinal cord disease, including tumors, or abnormalities by magnetic resonance imaging (MRI) or computerized tomography (CT) that would interfere with the lumbar puncture (LP) procedures or CSF circulation
  14. Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients
  15. Known allergy or hypersensitivity to iodine or iodine-containing products
  16. Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as adalimumab, or immunosuppressive therapy within 3 months of study dosing (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin, rituximab)
  17. Inability to withhold use of laxatives or diuretics in the 24 hours prior to dose administration
  18. Anti-AAV9 antibody titers >1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay
    • Should a potential patient demonstrate anti-AAV9 antibody titer > 1:50, he or she may receive retesting within 30 days of the screening period and will be eligible to participate if the anti-AAV9 antibody titer upon retesting is ≤ 1:50
  19. Abnormal laboratory values considered to be clinically significant (INR >1.4), GGT >3XULN, Bilirubin ≥3.0 mg/dL, Creatinine ≥1.0 mg/dL, Hgb <8 or >18 g/Dl; WBC >20,000 per cmm) prior to study dosing
  20. Participation in recent SMA treatment clinical trial or receipt of an investigational or approved compound product or therapy received with the intent to treat SMA (e.g., valproic acid, nusinersen) at any time prior to screening for this study
    • Oral beta agonists must be discontinued 30 days prior to dosing.
    • Inhaled albuterol specifically prescribed for the purposes of respiratory (bronchodilator) management is acceptable and not a contraindication at any time prior to screening for this study
  21. Expectation of major surgical procedures during the 1 year study assessment period (e.g., spinal surgery or tracheostomy)
  22. Inability or unwillingness to comply with study procedures or inability to travel for repeat visits
  23. Unwillingness to keep study results/observations confidential or to refrain from posting confidential study results/observations on social media sites
  24. Refusal to sign consent form

Contact Information:

Markus McColly
Clinical Research Coordinator II
Markus.McColly@nationwidechildrens.org
(614) 355-2825

Learn More at ClinicalTrials.org

General Studies

A 48-Week Open Label Study to Evaluate the Efficacy and Safety of Casimersen, Eteplirsen and Golodirsen in Subjects with Duchenne Muscular Dystrophy

Principal Investigator: Kevin M. Flanigan, MD

Co-Investigator: Megan Waldrop, MD

Enrollment Status: Not Yet Recruiting

Time Commitment: 2-8 weeks for screening procedure which includes 1-2 visits. Once a patient has passed all screening tests, the study will last about one year. This includes 15 study visits and weekly infusions of the drug.

Background: This is a study to find medications that can help treat Duchenne muscular dystrophy (DMD).  DMD is caused by a change (mutation) in a gene that does not make a properly functioning protein called dystrophin which protects the muscle from breaking down. There are many different mutations that can cause dystrophin to not function properly. Certain mutations are deletions (missing pieces) in portions of dystrophin and other mutations are duplications (or repeated pieces) in portions of the protein. Both types of mutations, deletions and duplications, can interfere with dystrophin protein function and cause DMD. There are three different drugs that are in clinical trials or are approved by the FDA to treat patients with certain deletion mutations. These drugs are called casimersen,  eteplirsen, and golodirsen. Now doctors want to test if these drugs are also safe and effective in patients with certain duplication mutations.

Purpose: This study will investigate if drugs tested previously in patients with certain deletion mutations are safe and helpful in subjects with certain duplication mutations. In this study, participants with certain duplications will be given the appropriate drug to remove the extra duplications in the dystrophin gene so that they could make normal dystrophin protein. This is an open-label, 48-week study to evaluate the effectiveness and safety of three phosphorodiamidate morpholino oligomers (PMOs) (casimersen, exondys 51 (eteplirsen), and golodirsen) in subjects with genetically confirmed Duchenne muscular dystrophy (DMD) with specific duplication mutations.

Inclusion Criteria:

  1. Is a male with DMD and has an out-of-frame duplication of either exon 45, 51, or 53, with a normal copy number of all other DMD exons.
  2. Is above age 6 months.
  3. Has pulmonary function, that in the Investigator’s opinion, is unlikely to decompensate significantly over the duration of the study.
  4. Has sufficient muscle mass in a pair of bilateral muscles that will allow for pre- and post-treatment muscle biopsies per PI discretion.
  5. If the subject is ambulant and 4 years old or greater and has been on a stable dose or dose equivalent of oral corticosteroids for at least 12 weeks prior to Week 1 the dose is expected to remain constant (except for modifications to accommodate changes in weight) throughout the study.

    Note: Subjects are allowed to take other medications (excluding other RNA antisense or gene therapy agents) including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blocking agents (ARBs), β adrenergic blockers, potassium, and coenzyme Q, provided they have been on a stable dose for 12 weeks prior to Week 1. The dose is expected to remain constant throughout the study (modifications to doses to accommodate changes in weight are allowed).

  6. Has (a) parent(s) or legal guardian(s) who is (are) able to understand and comply with all the study requirements.
  7. Is willing to provide informed assent (if applicable) and has (a) parent(s) or legal guardian(s) who is (are) willing to provide written informed consent for the subject to participate in the study.

Exclusion Criteria: A subject who meets any of the following criteria will be excluded from this study.

  1. Any additional missing exon for DMD that cannot be treated with study drugs.
  2. Subject has been treated with eteplirsen, or is amenable to or is currently being treated with other RNA antisense or gene therapy agents.
  3. Current or history of liver disease or impairment including:
    • An INR value above 1.5
    • A total bilirubin greater than 2 times the Upper Limit of Normal (ULN) or a GGT greater than 2 times the ULN
  4. Baseline platelet count below the Lower Limit of Normal (LLN) for age.
  5. aPPT above the ULN.
  6. History of significant medical disorder which may confound the interpretation of either efficacy or safety data e.g., inflammatory disease.
  7. Use of any pharmacologic treatment (other than corticosteroids) within 12 weeks prior to Week 1 that may have an effect on muscle strength or function (e.g., growth hormone, anabolic steroids).
  8. Current or previous treatment with any other experimental treatment within 12 weeks prior to Week 1.
  9. Major surgery within 3 months prior to Week 1 or planned surgery for any time during this study, except for protocol-specified surgery, as applicable.
  10. Presence of other clinically significant illness including significant cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease, or malignancy.
  11. Use of any aminoglycoside antibiotic or statin within 12 weeks prior to Week 1 or anticipated need for an aminoglycoside antibiotic or statin during the study.
  12. QTcF ≥ 450 msec based on the Screening and/or Baseline ECG.
  13. Prior or ongoing medical condition that could, in the Investigator’s opinion, adversely affect the safety of the subject, make it unlikely that the course of treatment would be completed, or impair the assessment of study results. Additionally, subjects who seem unable/unwilling to comply with the study procedures, in the Investigator’s opinion, are to be excluded.
  14. Acute illness within 4 weeks of the first anticipated administration of study medication which may interfere with study assessments.
  15. Symptomatic cardiomyopathy. If the subject is asymptomatic but has a left ventricular ejection fraction <40% at Screening, the investigator should discuss inclusion of subject in the study with the medical monitor.
  16. Use of anticoagulants, antithrombotics or antiplatelet agents, previous treatment with investigational drugs within 4 weeks prior to anticipated study drug administration.

Note: Potential subjects with abnormal laboratory values may be re-screened for specific laboratory tests within the screening period (the 45 days prior to dosing) before being designated a screen failure.  Repeat values within the normal range will be acceptable for inclusion. Additionally, if a subject should have an acute illness within 4 weeks of the first anticipated dose, the PI will discuss with the SRC about the potential to delay treatment until the illness has resolved.

Contact Information:

Clinical Research Service
CRSHelps@nationwidechildrens.org
(614) 722-2650

Additional Trials Using the Same Drug:

Learn more about Sarepta Therapeutics

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Ataluren in Patients with Nonsense Mutation Duchenne Muscular Dystrophy and Open-Label Extension

Sponsor: PTC Therapeutics

Principal Investigator: Kevin Flanigan, MD

Enrollment Status: Recruiting by invitation

Time Commitment: 2 years of treatment with 1 day clinic visits every 12 weeks for the duration of treatment in addition to a general health and end of study visit when the treatment with Ataluren is discontinued either at the end of the study or for any reason before.

Background: Dystrophin is a protein that keeps muscles healthy by maintaining structure of muscle cells. One type of mutation in the dystrophin gene is called a nonsense mutation. This type of mutation is the cause of DMD in about 15% of boys with the disease. A nonsense mutation results is a shortened dystrophin protein that does not work properly and leads to weakened muscles.  Ataluren is a drug thatpromotes muscle cells to make full length dystrophin protein.

Purpose: Doctors will continue to test the safety and effectiveness of the drug Ataluren in boys with DMD over the course of 2 years of treatment.

Inclusion Criteria: To be included in this research study, your child must have completed the PTC124-GD-020-DMD study. Your child’s doctor will carefully review the health status to make sure that he meets the necessary conditions for participation.  In addition, the patient must meet these criteria.Male sex.

  1. Age ≥5 years.
  2. Phenotypic evidence of DMD based on the onset of characteristic clinical symptoms or signs (eg, proximal muscle weakness, waddling gait, and Gowers’ maneuver) by 6 years of age and an elevated serum creatine kinase (CK).
  3. Documentation of the presence of a nonsense point mutation in the dystrophin gene as determined by gene sequencing.
  4. Use of systemic corticosteroids (prednisone/prednisolone or deflazacort) for a minimum of 12 months immediately prior to start of study treatment, with no significant change in dosage or dosing regimen for a minimum of 3 months immediately prior to start of study treatment and a reasonable expectation that dosage and dosing regimen will not change significantly for the duration of the study.

Exclusion Criteria:

  1. Any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation, or reinitiation) in prophylaxis/treatment for cardiomyopathy within 1 month prior to start of study treatment.
  2. Ongoing intravenous (IV) aminoglycoside or IV vancomycin therapy.
  3. Prior or ongoing therapy with ataluren.
  4. Known hypersensitivity to any of the ingredients or excipients of the study drug
  5. Exposure to another investigational drug within 6 months prior to start of study treatment, or ongoing participation in any interventional clinical trial
  6. History of major surgical procedure within 12 weeks prior to start of study treatment, or expectation of major surgical procedure (eg, scoliosis surgery) during the 72-week study period.

Contact Information:

Clinical Research Services
(614) 722-2650
CRSHelps@nationwidechildrens.org

Learn More on ClinicalTrials.gov

FOR-DMD: Finding the Optimal Steroid Treatment for Duchenne Muscular Dystrophy

Principal Investigator: Robert Griggs, MD University of Rochester

Nationwide Children’s Hospital Investigator: Kevin Flanigan, MD

Sponsor: University of Rochester

Enrollment Status: Active, not recruiting

Time Commitment: 5 years, active follow-up

Background: The FOR DMD study is a five year study that is taking place in at least 40 muscle clinics in the US, Canada, UK, Germany and Italy. The study is looking at the benefits and side effects of the three most widely prescribed corticosteroid treatments for Duchenne muscular dystrophy (DMD): daily prednisone, daily deflazacort, and intermittent prednisone. Corticosteroids are currently the only medicine that is known to delay the loss of ambulation in boys with DMD over a limited period of time, although how well these treatments work can be different for each patient.

Purpose: To determine what steroid treatment regimen is best tolerated and most beneficial for boys with DMD.

Inclusion Criteria:

Study participants must be:

  1. Diagnosed with Duchenne Muscular Dystrophy
  2. male
  3. 4-7 years old
  4. Not have previously been treated with oral steriods
  5. Ability to rise independently from floor, from supine to standing
  6. Willingness and ability to comply with scheduled visits, drug administration plan and study procedures
  7. Ability to maintain reproducible FVC measurements.

Exclusion Criteria:

  1. History of major renal or hepatic impairment, immunosuppression or other contraindications to corticosteroid therapy.
  2. History of chronic systemic fungal or viral infections. Acute bacterial infection (including TB) would exclude from enrolment until the infection had been appropriately treated and resolved.
  3. Diabetes mellitus.
  4. Idiopathic hypercalcuria.
  5. Lack of chicken pox immunity and refusal to undergo immunization.
  6. Evidence of symptomatic cardiomyopathy at screening assessment (one to three months prior to the baseline visit). Asymptomatic cardiac abnormality on investigation would not be an exclusion.
  7. Current or previous treatment (greater than four consecutive weeks of oral therapy) with corticosteroids or other immunosuppressive treatments for DMD or other recurrent indications (e.g., asthma), unless approved by FOR-DMD Team (i.e., concurrent participation in another allowed DMD trial).
  8. Inability to take tablets, as assessed by the site investigator by the end of the screening period (the screening period ranges from one to three months prior to the baseline visit).
  9. Allergy/sensitivity to study drugs or their formulations including lactose and/or sucrose intolerance.
  10. Severe behavioral problems, including severe autism.
  11. Previous or ongoing medical condition, medical history, physical findings or laboratory abnormalities that could affect safety, make it unlikely that treatment and follow up will be correctly completed or impair the assessment of study results, in the judgment of the site investigator.
  12. Weight of less than 13 kilograms.
  13. Exposure to any investigational drug currently or within 3 months prior to start of study treatment.

Contact Information:

Allie Fenter, Clinical Research Coordinator
Allie.Fenter@nationwidechildrens.org
(614) 355-2759

Learn more about FOR-DMD.

Learn More at ClinicalTrials.gov

A Double-Blind, Placebo-Controlled, Multicenter Study with an Open-Label Extension to Evaluate the Efficacy and Safety of SRP-4045 & SRP-4053 in Patients with Duchenne Muscular Dystrophy (DMD)

Principal Investigator: Jerry R Mendell, MD

Sponsor: Sarepta Therapeutics, Inc.

Enrollment Status: Not recruiting

Time Commitment:

  • Screening/Baseline Period: Up to 8 weeks
  • Double-Blind Placebo-Controlled Treatment Period: Up to 96 weeks, or less (depending on the outcome of an interim analysis at Week 48).
  • Open-Label Treatment Period: Up to an additional 96 weeks. Safety Follow-up Period: Approximately 4 weeks (28 days) following last infusion.
  • Total patient participation: Up to 204 weeks

Background: Dystrophinopathies are named after diseases that are caused by mutations of the dystrophin gene which is located on the X chromosome. Duchenne muscular dystrophy (DMD) is associated with the most severe clinical symptoms among all. Histologic and laboratory evidence of a myopathy may be observed from birth, but clinical onset occurs between two and three years of age. Proximal muscle weakness before the distal, and the lower before the upper extremities are present almost every patient with DMD. The affected child therefore has difficulty running, jumping, and walking up steps. When arising from the floor, affected boys may also use hand support to push themselves to an upright position, an action termed Gower's sign. An unusual waddling gait, lumbar lordosis, and calf enlargement are usually observed. Leg pain and cramps are common complain among DMD patients. Other motor signs and symptoms that may be present include toe walking, decreased endurance, decreased head control when pulled to sit, flat feet, frequent falls, clumsiness, gross motor delay, inability to keep up with peers, and loss of motor skills.

Other associated problems with DMD are elevated creatinine kinase (CK) and transaminases, growth delay, cardiomyopathy, orthopedic complications, and cognitive and behavioral disorders. Most patients become wheelchair bound by the age of twelve and die in their late teens or twenties from respiratory insufficiency or cardiomyopathy; only a few DMD patients survive beyond the third decade.

Two most common form of genetic impairments in Duchenne are deletions/ duplication, and point mutation. Currently available mainstay of pharmacologic treatment for DMD is Glucocorticoids.

Purpose: To evaluate the effect of SRP-4045 and SRP-4053 (combined-active group) compared to placebo on ambulation, endurance, and muscle function as measured by the 6-minute walk test (6MWT).

Also to evaluate:

  • Dystrophin protein expression in biopsied muscle tissue
  • Functional status of the subject (measured by various means including respiratory function)
  • Safety and tolerability of SRP-4045 and SRP-4053

Inclusion Criteria:

  1. Is a male with an established clinical diagnosis of DMD and an out-of-frame deletion amenable to:
    • Exon 45 skipping (including but not limited to deletions of exons such as 12-44, 18-44, 44, 46-47,46-48, 46-49, 46-51, 46-53, or 46-55) OR
    • Exon 53 skipping (including but not limited to deletions of exons such as 42-52, 45-52, 47-52, 48-52,49-52, 50-52, 52, or 54-58)

      As documented prior to screening by a genetic report from an accredited laboratory defining deletion endpoints by multiplex ligation-dependent probe amplification or sequencing. The patient’s amenability to exon 45 or 53 skipping must be confirmed prior to first dose using the genotyping results obtained during Screening.
  2. Is between 7 and 13 years of age, inclusive, at randomization.
  3. Has stable pulmonary function (FVC % of predicted ≥50% and no requirement for nocturnal ventilation) that, in the Investigator’s opinion, is unlikely to decompensate over the duration of the study.
  4. Has intact right and left biceps brachii muscles (the preferred biopsy site) or 2 alternative upper arm muscle groups.
  5. Has been on a stable dose or dose equivalent of oral corticosteroids for at least 24 weeks prior to Week 1 and the dose is expected to remain constant throughout the study (except for modifications to accommodate changes in weight).
  6. If taking angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blocking agents (ARBs), adrenergic blockers, aldosterone receptor antagonists, potassium, or coenzyme Q, has been on a stable dose for at least 12 weeks prior to Week 1 and the dose is expected to remain constant throughout the study (except for modifications to accommodate changes in weight).
  7. Achieved a mean 6MWT distance of ≥300 to ≤450 meters (without assistance) at both the Screening and Baseline visits (prior to Week 1). The mean 6MWT distance at the Screening and Baseline visits is the average of 2 separate assessments on 2 consecutive days at each visit. The Baseline mean (average of Baseline Days 1 and 2) must be within 15% of the Screening mean distance (average of Screening Days 1 and 2).
  8. If sexually active, agrees to use a male condom during such activity for the entire duration of the study and for 90 days after the last dose. The sexual partner must also use a medically acceptable form of contraceptive (eg, female oral contraceptives) during this time frame.
  9. Has (a) parent(s) or legal guardian(s) who is (are) able to understand and comply with all the study requirements.
  10. Is willing to provide informed assent (if applicable) and has (a) parent(s) or legal guardian(s) who is (are) willing to provide written informed consent for the patient to participate in the study.

Exclusion Criteria:

  1. Treatment with any of the following investigational therapies according to the time frames specified:
    • At any time:
      • Utrophin upregulating agents (eg, ezutromid [SMT C1100] or other)
      • Anti-myostatin agents (eg, BMS-986089, domagrazumab [PF-062552616] or other)
      • CRISPR/Cas9, or any other form of gene editing
      • Gene therapy
      • Cell-based therapy (eg, stem cell transplantation)
      • Any form of nucleic acid antisense therapy, except PRO045 (BMN 045) or PRO053 (BMN 053) (see below)
    • Within 24 weeks prior to Week 1:
      • PRO045 (BMN 045)
      • PRO053 (BMN 053)
      • Anti-fibrotic or anti-inflammatory agents including but not limited to: rimeporide, vamorolone (VBP-15), epigallocatechin-gallate, TAS-205, edasalonexent (CAT-1004), FG-3019, and halofuginone (HT-100)
      • Mast cell activation inhibitor (eg, CRD007 [pemirolast sodium])
      • Idebenone (Raxone®)
    • Within 12 weeks prior to Week 1:
      • Nitric oxide (NO)-active agents including, but not limited to, metformin and citrulline, isosorbide dinitrate, tadalafil, sildenafil, pentoxyfilline if taken as part of a DMD clinical trial and not for a medical indication. If taken for a medical indication, must be on a stable dose for at least 12 weeks prior to Week 1.
    • For any experimental treatment not otherwise specified in Exclusion Criterion 1, consult the medical monitor.
  2. Treatment with any of the following non-investigational therapies according to the time frames specified:
    • Within 12 weeks prior to Week 1:
      • Any pharmacologic treatment (other than corticosteroids) that may have an effect on muscle strength or function. Growth hormone for short stature and testosterone for delayed puberty are permitted if a physician has documented the diagnosis and medical necessity of treatment, and the patient started dosing at least 24 weeks prior to Week 1.
    • Within 12 weeks prior to Week 1 or anticipated need during the study:
      • Statins
      • Aminoglycoside antibiotics
  3. Major surgery within 3 months prior to Week 1 or planned surgery for any time during this study, except for protocol-specified surgery, as applicable.
  4. Presence of any other significant genetic disease other than DMD (eg, dwarfism).
  5. Presence of other clinically significant illness including significant cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease, or malignancy.
  6. LVEF <50% on the Screening echocardiogram (ECHO) or QTcF ≥450 msec on the Screening and Baseline ECG.Sarepta 4553
  7. Dorsiflexion range of motion will be measured bilaterally and recorded as degrees from neutral (see figure). The subject will be excluded if the average loss of dorsiflexion of both extremities is > -10 degrees. For example, if the subject has -8 degrees on one side and -12 degrees on the other side, then he would still qualify because the average of the 2 sides is -10 degrees.
  8. Prior or ongoing medical condition that could, in the Investigator’s opinion, adversely affect the safety of the patient, make it unlikely that the course of treatment would be completed, or impair the assessment of study results. Additionally, patients who seem unable / unwilling to comply with the study procedures, in the Investigator’s opinion, are to be excluded.

Contact Information: 

Lauren Bird, RN
Clinical Research Coordinator
Lauren.Bird@nationwidechildrens.org
(614) 722-2699

Learn More at ClinicalTrials.gov

A Randomized Open Label Trial of Spironolactone Versus Prednisolone in Corticosteroid Naïve Boys with DMD

Sponsor: Muscular Dystrophy Association (MDA)

Principal Investigator: Kevin Flanigan, MD

Co-Investigator: Megan Waldrop, MD, Jerry Mendell, MD, Jill Rafael-Fortney, MD

Enrollment Status: Recruiting

Time Commitment: Up to 8 clinic visits over 6 months of treatment

Background: Steroids are the current treatment for Duchenne Muscular Dystrophy (DMD). One of the steroids used for treatment is prednisolone. Prednisolone prolongs the ability to walk, improves muscle strength and delays heart damage, but it does not cure DMD. Prednisolone also has significant side effects including excessive weight gain, redness of the skin, excessive hair growth and decreased bone length and strength.  This study will try to find out if it is safe to use a different medicine than prednisolone called spironolactone. This drug has been approved by the Food and Drug Administration for the use in treating patients with heart failure but not for the use that we will be looking at in this study. Spironolactone has been widely used in children with minimal side effects. In studies with mice that have a muscle disease, spironolactone reduces muscle damage and improves muscle function.  This study will not cure DMD but may slow the breakdown of muscles.

Purpose: The main goal of this study is to determine if spironolactone is safe to use in boys with DMD. This study is “open label”, which means that the Study Doctor, their staff, and patients and parents may know if they are receiving prednisolone or spironolactone. This is because prednisolone and spironolactone do not look or taste the same.

Inclusion Criteria:

  1. Duchenne muscular dystrophy patients ages ≥4 through ≤7 years
  2. Clinical features of DMD that include proximal predominant weakness and/or trouble walking 
  3. Presence of a truncating mutation of the DMD gene, or a muscle biopsy that demonstrates <5% dystrophin in the patient or an affected relative
  4. Normal left ventricular ejection fraction by screening echocardiogram
  5. Ability to cooperate for testing
  6. No prior glucocorticoid treatment
  7. No concomitant experimental therapies

Exclusion Criteria:

  1. Subject amenable to or currently being treated with eteplirsen
  2. Hyperkalemia at screening
  3. History of or ongoing renal failure (elevated creatinine, oliguria, anuria)
  4. Hypersensitivity to spironolactone (rash, respiratory distress, arrhythmia, numbness or tingling of extremities)
  5. Current treatment with an ACEi
  6. Severe peptic ulcer disease or recent gastrointestinal perforations

Contact Information:

Allie Fenter
Allie.Fenter@nationwidechildrens.org
(614) 355-2759

Tori Danneker
Victoria.Danneker@nationwidechildrens.org
(614) 722-5610

Outcomes Research

Development of Normative Data for the 100 and 60 Meter Test in Individuals with Muscle Disease and Controls

Principal Investigator: Linda Lowes, PhD

Enrollment Status: Recruiting

Time Commitment: 10 minutes

Background: Timed walking tests are often used as primary outcome measures in clinical trials in individuals with neuromuscular disease.  The 6-minute walk test (6MWT) is the most commonly used walking test but results of experimental treatments are difficult to interpret due to the large variability in 6MWT data.  In addition, recent data suggest that treatments may be more beneficial when started at a young age.  Collecting consistent results from a test that requires attention and best performance for 6-minutes is likely to cause problems in a younger cohort.  Thus, the need for a reliable walking test that encourages consistent results across a broad age range is critical.  The 100 meter walk/run test has been proposed as an outcome for neuromuscular disease, as it is a fixed distance and allows individuals to perform to the best of their ability. 

Purpose: The purpose of this study is to collect 100 meter data in a cohort of individuals with motor difficulties and age matched controls in order to develop normative data in these populations. 

Inclusion Criteria:

  • Ages 4 to 99
  • Ability to follow directions and willingness to participate in study procedures

Exclusion Criteria:

  • Lower limb injury or other medical condition that could affect performance of study procedures

Contact Information:

Neuromuscular Physical Therapy
NMDtrialinfo@nationwidechildrens.org
(614) 722-6881

Utility of Markerless Video Tracking to Assess Movement

Principal Investigator: Linda Lowes, PhD

Enrollment Status: Recruiting

Time Commitment: Active follow-up over 2 years

Background: Traditional infant assessments are great at identifying infants that are not following typical development.  However, when a child is significantly delayed, the traditional assessments document an extremely low score that will never change because the progression of these sick infants is small and slow.  ACTIVE-mini (Abilities Captured Through Interactive Video Evaluation) is a motor assessment tool that uses the Microsoft Kinect sensor and color tracking technology to record a child’s movements.  Latex free, colored wraps are placed on the hands and feet of the child while they lie on a mat and are motivated to move their extremities.  ACTIVE-mini can be used in a research or clinical setting as a functional assessment that is able to determine small, meaningful changes in movement that would otherwise be undetected by traditional assessments.  

Purpose: The purpose of this study is to investigate the validity and reliability of the ACTIVE-mini assessment as a motor function tool in a cohort of infants with motor deficits and age-matched controls.

Inclusion Criteria:

  • Ability to tolerate lying on back for a minimum of two minutes

Exclusion Criteria:

  • Ability to roll

Contact Information:

Neuromuscular Physical Therapy
NMDtrialinfo@nationwidechildrens.org
(614) 722-6881

Utility of Markerless Video Tracking to Assess Movement

Principal Investigator: Linda Lowes, PhD

Enrollment Status: Recruiting

Time Commitment: 10 minutes

Background: Experimental trials typically use timed walking tests as a functional outcome measure due to ease of administration and a body of literature investigating the reliability and validity of these outcomes.  However, this means that children who cannot walk are not eligible for participation in these trials.  In addition, outcome measures that address function in the upper extremity often fail to be sensitive enough to capture changes over time.  This leaves a large unmet need for populations with neuromuscular disease because upper body movement is essential for most activities that impact an individual’s quality of life.  ACTIVE-Seated (Abilities Captured Through Interactive Video Evaluation) is a video game that utilizes the Microsoft Kinect sensor to measure functional reaching volume while the patient is motivated to squish spiders or collect gems.  ACTIVE measures the ability for an individual to perform activities of daily living that greatly improve quality of life, such as the ability to perform self-care tasks.  Therefore, it can be utilized in a clinical or research setting as a sensitive outcome measure that can be used in both ambulatory and non-ambulatory populations.   

Purpose: The objective of this study is to investigate the validity and reliability of the ACTIVE-Seated system to evaluate the upper extremity and trunk mobility of children and adults with motor deficits and typically developing peers. 

Inclusion Criteria:

  1. Ability to follow directions and understand the video game
  2. Ability to provide informed consent

Exclusion Criteria:

  1. Unable to be positioned in sitting with less than 30 degrees recline
  2. Inability to move at least one portion of the upper extremity ( arm, wrist, or fingers)
  3. Health condition that would interfere with the subject’s ability to participate

Contact Information:

Neuromuscular Physical Therapy
NMDtrialinfo@nationwidechildrens.org
(614) 722-6881

Biomarker Biobanking in Neuromuscular and Neurological Diseases

Principal Investigator: Kevin Flanigan, MD

Enrollment Status: Active, Recruiting

Time Commitment: 1 visit per blood draw

Background: We are interested in learning more about neuromuscular diseases. To do this, we are working to establish a bank of blood samples from patients with neuromuscular and neurological diseases. We will also collect samples from people without neuromuscular diseases for a healthy control comparison. This collection of samples will be used for a variety of research projects primarily in the laboratories of investigators here at NCH, but if applicable will be shared with other institutes. These studies could help researchers identify biomarkers, which are genes that change when a disease is present. Biomarkers can also be used to predict if a treatment will work or not. Another goal of this study is to continue to learn more about the body’s immune response in the context of gene therapies. We hope these projects will give us more information about the pathways and progression of neuromuscular diseases. 

Purpose: The primary objective is to establish a bank of collected blood (serum, plasma, whole blood, and RNA) from patients with neuromuscular or neurological diseases, to be used to discover new biomarkers and/or validate them as well as continue to learn about the body’s immune response to gene therapy.

Inclusion Criteria:

Study Participants must meet one or more of the following:

  1. Patients diagnosed with a neuromuscular or neurological disease
  2. Suspected to have a neuromuscular or neurological disease
  3. Any healthy volunteer to serve as a control

Exclusion Criteria:

  1. Subjects cannot participate if taking medications that suppress the immune system
  2. Subjects cannot participate if enrolled in a treatment clinical trial

Contact Information:

Roxane Alles, Clinical Research Program Coordinator
Roxane.Alles@nationwidechildrens.org
(614) 355-3003

Duchenne Muscular Dystrophy (DMD)/Becker Muscular Dystrophy (BMD) Carrier Detection Study

Principal Investigator: May Ling Mah, MD

Sponsor: Parent Project Muscular Dystrophy

Enrollment Status: Recruiting

Time Commitment:  Active follow-up over 2 years

Background: It is not surprising that DMD/BMD carriers are at risk for muscular dystrophy manifestations. The risks fall into three clinical categories: cardiac, skeletal and cognitive. The molecular mechanism for carrier manifestations has always been assumed to be nonrandom X chromosome inactivation (XCI). XCI cannot explain the majority of symptoms in DMD/BMD carriers. In addition, XCI does not fully explain the spectrum of clinical phenotype (asymptomatic, mild or severe disability), nor the predominance in mutation type. Most DMD/BMD carrier studies have focused on cardiac manifestations because they can be life threatening. In this study, newer technology will now help us better define the abnormalities in the heart and let us prioritize those that would be the most predictive of future clinical manifestations. Skeletal muscle involvement ranges from fully manifesting carriers with significant muscle weakness to those with asymptomatic involvement. Unfortunately, as with cardiac manifestations, XCI will not predict the degree of muscle weakness in DMD carriers. The exact incidence of cognitive impairment in carriers is not well defined. However, symptomatic DMD carriers who have cognitive impairment are known to have a predilection for mutations in the distal part of the DMD gene.

Purpose: To understand and characterize cardiac, skeletal, and cognitive risks of DMD/BMD carriers.

Inclusion Criteria:

  1. Age >18 years
  2. Cohort A requires a genetically confirmed mutation in the DMD gene with an affected child
  3. Cohort B includes DMD/BMD mothers with NO somatic mutation in the DMD gene
  4. Cohort C age-matched healthy controls with a normal CK level
  5. Cohort D requires a genetically confirmed mutation in the DMD gene without having an affected child
  6. Able to complete testing in English
  7. Able to consent

Exclusion Criteria:

  1. Subjects with a contraindication to cardiac MRI
  2. Subjects on steroid treatment
  3. Presence of an inherited neurologic disease or comorbidity that may affect their ability to complete this study
  4. Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject’s ability to comply with the protocol required testing or procedures or compromise the subject’s wellbeing, safety, or clinical interpretability.
  5. Pregnancy any time during the study; a female subject judged by the investigator to be of childbearing potential will be tested for pregnancy due to the possible risks. Pregnant subjects will be excluded from this study due to the potential risks the treadmill and MRI contrast studies may pose on the fetus.

Contact Information:

Eric Camino, PhD
Clinical Research Coordinator II
Eric.Camino@nationwidechildrens.org
(614) 722-2715

Learn More at ClinicalTrials.gov

Utility of Physical Activity Trackers in Children with a Motor Deficit/Duchenne Muscular Dystrophy

Principal Investigator: Linda Lowes, PhD

Enrollment Status: Recruiting

Time Commitment: Active follow-up over 2 years

Background: Duchenne muscular dystrophy is an X-linked neuromuscular disease that presents with muscle degeneration, impaired pulmonary status, and decreased cardiac function.  Currently, there is no cure for this disease, however, experimental treatments are being tested in clinical trials.  Timed walking tests are typically used as a primary outcome measure in clinical trials within the DMD population.  In recent clinical trials, parents and subjects have reported positive effects of the treatment, including increased physical activity, that were not detected by the outcome measures.  Therefore, there is a need to detect small, meaningful changes in daily function in order to serve as a measure of efficacy in clinical trials.  Physical activity tracers are designed to assess physical activity levels during daily activities and many models are now commercially available.  They have been validated as a measure of activity in children with motor deficits such as cerebral palsy and could potentially be used to measure activity levels of boys with DMD. 

Purpose: The objective of this study is to assess the feasibility and utility of a commercially available physical activity tracker to determine physical activity levels in children with Duchenne Muscular Dystrophy and compare these results to performance on standard functional tests.  In addition, this study would compare the activity of children with DMD to the activity levels of age-matched peers.

Inclusion Criteria:

  1. Ages 4-25 years
  2. Confirmed diagnosis of DMD or other motor deficit
  3. Ability to follow directions and willingness to participate in study procedures

Exclusion Criteria:

  1. Evidence of current or previous lower limb injury that could affect performance of study procedures
  2. Medical condition or developmental history (i.e. concomitant illness, behavioral disorder, prematurity) that make it unsafe for the subject to participate or could impair study results.

Contact Information:

Neuromuscular Physical Therapy
NMDtrialinfo@nationwidechildrens.org
(614) 722-6881

The Center for Gene Therapy DNA Bank: Genetic and Molecular Characterization of Inherited Neurological Diseases

Principal Investigator: Kevin Flanigan, MD

Enrollment Status: Active, Recruiting

Time Commitment: 1 blood draw

Background: This study aims to determine the genetic causes of inherited neurological disorders in patients and their families. To do this, DNA is isolated from a participant’s blood and/or saliva. This DNA is then used to find out what gene is responsible for that patient’s disease. A gene is a coded piece of information that is present in every cell in your body. It contains information that is required for some portion of your body to do its job. When a gene contains an error in its code, it is said to have a mutation. Mutations may be passed along from one generation to the next in the same family. This work will help us understand the cause of neuromuscular disorders and may lead to the development of treatments.

Purpose: To collect blood/saliva that will be stored, preserved and used to better understand inherited neurologic disease, for teaching purposes, and for approved future research studies. In this study, we will examine your blood/saliva samples to determine the gene mutation responsible for the condition that runs in a participating family. This will allow us to better understand how the disease develops and might help us develop therapies.

Inclusion Criteria:

Study Participants must meet one or more of the following:

  1. Diagnosed with a neuromuscular or neurological disease
  2. Suspected to have a neuromuscular or neurological disease
  3. A family member of the patient if deemed eligible by investigator

Exclusion Criteria:

  • There are no exclusion criteria

Contact Information:

Federica Rinaldi, Clinical Research Program Coordinator
Federica.Rinaldi@nationwidechildrens.org
(614) 355-2897

Use of Body-Weight Support Harness Systems to Facilitate Motor Milestone Development in Children with Spinal Muscular Atrophy

Principal Investigator: Megan Iammarino, DPT

Enrollment Status: Recruiting

Time Commitment: Participants will be given a body weight support harness system to use in their home over a period of 3 months

Background: Spinal muscular atrophy (SMA) is an autosomal recessive disease involving the degeneration of lower motor neurons in the spinal cord that results in muscle atrophy.  Historically, the approach of treatment is aimed at limiting decline through management of clinical symptoms.  This approach is quickly changing as recent therapeutic advancements are making their way through the clinical trial pipeline and achievement of gross motor milestones beyond what would be expected are reported.  These reported successes are also changing the aims of physical therapy interventions to be geared toward motor milestone and gross motor development.  Typically developing children build strength and motor skills by exploring their environment but children with SMA have motor deficits that limit their ability to explore their environment.  By unweighting a portion of their body weight, children with SMA can begin to use muscles in their legs and trunk, which they would otherwise be unable to do. Daily in-home use of a body weight support harness system may assist these children in building strength and developing new skills.    

Purpose: The purpose of this study is to investigate the effects of a home-based functional exercise program using a body weight support harness system on motor milestone development in children with SMA.

Inclusion Criteria:

  1. Able to safely fit in pediatric harness
  2. Genetic diagnosis of SMA
  3. Delay in standing or walking
  4. Able to right head from full flexion

Exclusion Criteria:

  1. A body weight greater than 50 lbs
  2. Current or previous lower limb injury or fractures within the past 6 months
  3. Medical condition or developmental history (i.e. concomitant illness, behavioral disorder, prematurity, uncontrolled seizure disorder) that make it unsafe for the subject to participate or could impair study results

Contact Information:

Neuromuscular Physical Therapy
NMDtrialinfo@nationwidechildrens.org
(614) 722-6881

Limb Girdle Muscular Dystrophy Type 2E Recruitment Study

Principal Investigator: Jerry R. Mendell, MD

Sponsor: Myonexus Therapeutic

Enrollment Status: Recruiting

Time Commitment: Active follow-up over 2 years

Background: LGMD2E is one of the variants of Limb Girdle Muscular Dystrophies (LGMD). LGMD2E is caused by a non-working β-sarcoglycan gene that results in the body not making a properly functioning protein that is also called beta-sarcoglycan. When β-sarcoglycan protein is absent or changed, the muscle membrane can be damaged. Proteins are the building blocks of all tissues. They are produced by genes that are found in your body. If a gene is not working, it will not make the correct protein or enough of it. This can include proteins needed by muscles which can cause a disease like muscular dystrophy. LGMD2E typically presents with difficulty running, jumping and climbing stairs within the first decade of life. Cardiac involvement is commonly seen in this disease. There is currently no established treatment for LGMD2E.

Purpose: This recruitment study will try to find out how the disease changes over time and the effects of the disease. The association between functional impairment and long-term outcomes, such as loss of mobility, falls, and quality of life, will be examined. Consecutive measurements will be obtained. These measurements can show whether or not a patient will be eligible for the LGMD2E gene therapy trial.

Inclusion Criteria:

  1. Age 3-15 inclusive
  2. Males or females of any ethnic group
  3. SGCB DNA gene mutations at both alleles or suspected to have LGMD2E based on family and medical history. If suspected, genetic testing will be performed to confirm diagnosis.
  4. Weakness demonstrated based on history of difficulty running, jumping and climbing stairs
  5. Ability to complete 100MW timed test within 30-90% predicted
  6. Perform assessments to the best of their ability with reliable results as deemed by the evaluator.
  7. Ability to attend scheduled appointments
  8. Ability to provide informed consent (or assent for ages 9-15)

Exclusion Criteria:

  1. Confirmed diagnosis of neuromuscular disorder other than LGMD2E
  2. Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject’s ability to comply with the protocol required testing or procedures or compromise the subject’s wellbeing, safety, or clinical interpretability
  3. Subjects with AAVrh74 binding antibody titers > 1:400 as determined by ELISA immunoassay. If endpoint titer is positive at screening, testing may be repeated in 1 month. Antibody testing will be performed on a separate study
  4. Diagnosis of (or ongoing treatment for) an autoimmune disease

Contact Information:

Stephanie Diemer, MS
Clinical Research Coordinator II
Stephanie.Diemer@nationwidechildrens.org
(614) 355-2679

Evaluation of Muscle and Skin for the Study of Inherited Neurologic Diseases

Principal Investigator: Kevin Flanigan, MD

Enrollment Status: Active, Recruiting

Time Commitment: 1 visit for biopsy procedure or no visits for participants allowing an archived sample to be shared with NCH or allowing for a muscle sample to be taken during a clinical procedure.

Background: A neurologic or neuromuscular disorder is caused by an abnormality in a gene in your body that produces either a faulty protein or no protein at all. Frequently, a small piece of tissue is needed from a patient to fully characterize a diagnosis. The procedure to obtain this tissue is called a biopsy. Two tissues—muscle and skin—are routinely and safely biopsied for these purposes. In addition, muscle and skin biopsies provide a good way for researchers to learn more about these disorders. To do this, DNA, RNA (the building blocks of genes) and proteins from the muscle and skin samples are extracted for study. Also, the skin and muscle specimens can be used to establish cell cultures that can be used over long periods of time for studies. Muscle and skin specimens can also be examined under a microscope to better understand differences between normal tissue and tissue from an individual affected with muscle disease.

Purpose: Collect muscle and/or skin to store, preserve and use to better understand neurologic diseases, for teaching purposes, and for approved future research studies.

Inclusion Criteria:

Study Participants must meet one or more of the following:

  1. Patients diagnosed with a neuromuscular or neurological disease
  2. Suspected to have a neuromuscular or neurological disease
  3. Any healthy adult volunteer can serve as a control

Exclusion Criteria:

  • Subjects cannot participate if their blood does not clot normally.

Contact Information:

Carlee Giesige
Clinical Research Coordinator
Carlee.Giesige@nationwidechildrens.org
(614) 355-2727

Natural History of Disease Progression in Individuals with Neuromuscular Disorders

Principal Investigator: Linda Lowes, PhD

Enrollment Status: Recruiting

Time Commitment: Active follow-up over 2 years

Background: Neuromuscular disease typically presents with weakened muscles, difficulty breathing, and decreased cardiac function. These neuromuscular disorders can be rare, and therefore difficult to establish a natural progression of each disease. The natural history of each neuromuscular disorder provides valuable information that can guide in understanding which outcome measure to use in order to show change for clinical trials. Therefore, the need to detect small, meaningful changes in daily activities in order to show efficacy in clinical trials is of great importance.

Purpose: The purpose of this study is to better understand how neuromuscular diseases change over time and how they affect the ability for an individual to perform daily tasks. Participants will be asked to complete several functional tests that look at walking ability, strength, and movement. The results from this study will help to define the natural history of disease and help to identify potential candidates for future trials. This is an observational study, no drug (marketed or investigational) will be provided for treatment.

Inclusion Criteria:

  1. Ages 0-99 years
  2. Suspected neuromuscular disorder by symptoms and/or having a family member diagnosed with a neuromuscular disorder, or have genetic confirmation of a neuromuscular disorder
  3. Perform assessments to the best of their ability with reliable results as deemed by the evaluator
  4. Ability to attend scheduled appointments

Exclusion Criteria:

  1. Confirmed diagnosis of another disorder other than a neuromuscular disorder
  2. Has a medical condition or extenuating circumstance that might compromise the subject’s ability to comply with the required testing, procedures, or compromise the subject’s well being or safety.

Contact Information:

Neuromuscular Physical Therapy
NMDtrialinfo@nationwidechildrens.org
(614) 722-6881

A Prospective, Long-Term Registry of Patients with a Diagnosis of Spinal Muscular Atrophy

Sponsor: AveXis

Principal Investigator: Megan Waldrop, MD

Co-Investigator: Kevin Flanigan, MD

Enrollment Status: Active, Recruiting

Time Commitment: no additional visits, surveys can be completed at home and functional tests will be performed during regular visits

Background: SMA is a neurological disorder caused by a loss or mutation in the survival motor neuron 1 gene (SMN1). SMA is an early childhood disease and is the leading cause of infant mortality due to genetic disease. Until now, treatment of these patients has focused on supportive care and treatments that improved disease symptoms were unavailable. However, recent advances in treatments including gene replacement and ways to protect nerve and muscle function may lead to significant change in the care of these patients and their disease symptoms.

Purpose: The purpose of this registry is to follow SMA patients over 15 years to study if the treatments that are now available are changing how SMA affects children with this disease. Specifically, doctors want to measure if the treatments available are safe over long periods of time and if they help patients live longer.

Inclusion Criteria:

  • Patients with a genetic confirmation of SMA

Exclusion Criteria:

  • There are no exclusion criteria for this registry

Contact Information:

Jessica Noel-Morgan
Jessica.Noel-Morgan@NationwideChildrens.org
(614) 355-3428

United Dystrophinopathy Project

Principal Investigator: Kevin Flanigan, MD

Enrollment Status: Active, recruiting

Time Commitment: No additional visits

Background: Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD) are caused by changes in the dystrophin gene. Changes in the gene, called mutations, can cause the dystrophin protein to be only partially made or completely missing in patients with DMD and BMD. This leads to muscle weakness. Different dystrophin mutations can cause patients with DMD and BMD to have different levels of muscle weakness when comparing one patient to the next. In addition to dystrophin mutations, mutations in other genes can contribute to the severity and progression of the disease. We have not identified all of the genes that could contribute to or modify the symptoms in each DMD or BMD patient.  It is not fully understood how these mutations in dystrophin and other genes affect the severity and progression of the disease.

Purpose: This study’s goal is to identify modifying genes and understand how different mutations in the dystrophin gene and in other genes determine the symptoms and degree of muscle weakness. This in turn can improve our ability to predict a patient’s disease progression over time and tailor each patient’s treatment accordingly. To do this, we are establishing a database of patients with dystrophinopathies (including Duchenne and Becker muscular dystrophy, as well as female carriers of DMD mutations). This database will include information about the dystrophin gene mutation of the patient, disease symptoms and how these symptoms change over time. This information will be gathered through a questionnaire that will be updated during normal doctor’s visits. Additionally, participants can choose to share a blood sample that was previously taken or give a new saliva sample that we can use to extract the DNA from in order to study their genes. We will use this DNA sample to test for variations in genes that might influence the severity of their muscular dystrophy.

Inclusion Criteria:

Study Participants must meet one or more of the following:

  1. Diagnosed with a dystrophinopathy
  2. Suspected to have a dystrophinopathy
  3. A female carrier of a dystrophin mutation

Exclusion Criteria:

There are no exclusion criteria.

Contact Information:

Roxane Alles
Clinical Research Program Coordinator
Roxane.Alles@nationwidechildrens.org
(614) 355-3003

 

Spinal Muscular Atrophy

Phase I/IIa Gene Therapy Trial for Treatment of Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A)

Principal Investigator: Zarife Sahenk, MD, PhD, Nationwide Children’s Hospital

Sponsor: NIH, National Institute of Neurological Disorders and Stroke (NINDS)

Enrollment Status: Not Recruiting

Time Commitment: 2 years

Background: Charcot-Marie-Tooth (CMT) hereditary neuropathy is a group of disorders characterized by a chronic motor and sensory polyneuropathy, also known as hereditary motor and sensory neuropathy (HMSN). These disorders are caused by gene mutations whose protein products are expressed in myelin and/or axons of peripheral nerves. Different mutations within the same gene, which express various clinical phenotypes is a common finding in this group of neuropathies. The most common initial presentation of CMT is distal weakness and atrophy. Hence patients present with foot drop and pes cavus. Sensory symptoms are often present but tend to be less prominent. Later in the course, foot deformities such as hammertoes ensue, along with hand weakness and atrophy becomes a challenges in treating CMT.

Traditionally, CMT classification was based on peripheral neuropathy (determined by nerve conduction velocity) and mode of inheritance. For example, CMT1, CMT2, DI-CMT (Dominant Intermediate). But recent evolving genetics has pushed for new CMT naming system based on gene involvement, which already been proposed.

CMT1A, most common form of CMT is associated with a 1.5 Mb duplication or, less commonly, a point mutation of the peripheral myelin protein 22 (PMP22) gene on chromosome 17p11.2-p1; duplication causes overexpression of PMP22, on the other hand, point mutations alter distribution of the protein. Patients with point mutations have has more prominent symptoms. Patients with CMT1A may have associated with sleep apnea. Ddiabetes mellitus, vitamin deficiencies, and immune-mediated neuropathies may further exacerbate CMT condition.

Currently there is no treatment for this condition.  Ascorbic acid supplements have been highly touted to help, but multiple studies have shown no benefit. A human trial of NT-3 provided by Regeneron showed clinical efficacy after 24 weeks of treatment accompanied by increased numbers of myelinated nerve fibers in post-treatment sural nerve biopsies.

Purpose: To evaluate the safety of administering neurotrophin-3 (NT-3) encoding NTF3 gene using self-complementary adeno-associated virus (scAAV) type. The safety of dose escalation will also be evaluated over the course of the study.

Inclusion Criteria:

  1. Subjects 15- 35 years old inclusive with CMT1A will be enrolled (Cohort 1 will only include subjects that are 18 to 35 years of age)
  2. All must exhibit a 1.5 Mb duplication at 17p11.2 inclusive of the peripheral myelin protein 22 (PMP22) gene
  3. Males and females of any ethnic or racial group
  4. Patients must exhibit weakness of the ankle dorsiflexion muscle (but have full range of motion (ROM) against gravity and able stand on heels for 3 seconds or greater)
  5. Abnormal nerve conduction velocities
  6. Ability to cooperate for clinical evaluation and repeat nerve conduction studies
  7. Willingness of sexually active subjects to practice a reliable method of contraception during the study

Exclusion Criteria:

  1. Active viral infection based on clinical observations or serological evidence of HIV, or Hepatitis B or C infection
  2. Ongoing immunosuppressive therapy or immunosuppressive therapy within 6 months of starting the trial (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin)
  3. Persistent leukopenia or leukocytosis (WBC ≤ 3.5 K/µL or ≥ 20.0 K/µL) or an absolute neutrophil count < 1.5K/µL
  4. Subjects with AAV1 binding antibody titers ≥ 1:50 as determined by ELISA immunoassay
  5. Subjects with circulating anti-NT-3 titers ≥ 1:50 as determined by ELISA immunoassay
  6. Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
  7. Treatment with any investigational medication within 30 days before the infusion of study drug
  8. Abnormal laboratory values considered clinically significant (GGT > 3XULN, bilirubin ≥ 3.0 mg/dL, creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/Dl; WBC > 15,000 per cmm)
  9. Ankle contractures or surgeries preventing proper muscle strength testing
  10. Pregnancy or lactation (female subjects will be tested for pregnancy)
  11. Limb surgery in the past six months
  12. Any medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject’s ability to comply with the protocol required testing or procedures or compromise the subject’s wellbeing, safety, or clinical interpretability
  13. Severe infection (e.g. pneumonia, pyelonephritis, or meningitis) within 4 weeks before gene transfer visit (enrollment may be postponed)
  14. Any subject unwilling to disclose patient's study participation with primary care physician and other medical providers
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