Gene Therapy Clinical Research

Principal Investigator: Anne M. Connolly, MD

Sponsor: Washington University School of Medicine

Enrollment Status: Ongoing study, not 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

Principal Investigator: Anne M. Connolly, MD

Sponsor: Sarepta Therapeutics

Enrollment Status: Ongoing study, not recruiting

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

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

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

Principal Investigator: Anne M. Connolly, MD

Sponsor: AveXis, Inc.

Enrollment Status: Ongoing study, not 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

Principal Investigator: Anne M. Connolly, MD

Sponsor: AveXis, Inc.

Enrollment Status: Ongoing study, not 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

Principal Investigator: Anne M. Connolly, MD

Sponsor: AveXis, Inc.

Enrollment Status: Ongoing study, not 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

Principal Investigator: Kevin M. Flanigan, MD

Co-Investigator: Samantha LoRusso, MD

Enrollment Status: Recruiting

Time Commitment: 2-3 days for all study visits. 

Background: Facioscapulohumeral muscular dystrophy (FSHD) is among the most common types of muscular dystrophy. Although the disease was named for the muscle groups most affected, there is no universal pattern of muscle involvement and patients can show wide variability in symptoms. FSHD is caused by aberrant expression of the double homeobox protein 4 (DUX4) gene which leads to unusual translation of the DUX4 protein. The DUX4 protein is toxic to muscle, cultured myocytes, and other non-muscle cells. DUX4 has historically been difficult to impossible to detect in patient samples, but we have developed a new method of detecting DUX4 expression in muscle biopsies. We hope to use this new method to correlate the expression of DUX4 in muscle with overall function and disease severity.

Purpose: This study will help investigators to understand the relationship between DUX4 expression in muscle from FSHD patients, and to understand how the molecular changes that result from DUX4 expression relate to the clinical symptoms of FSHD.  In order to do this, we need to study muscle strength and function, MRI changes in muscle, and changes of gene expression in biopsy tissue. This information may help us find new ways to treat FSHD. 

Inclusion Criteria: 

1. 18 years or older
2. Genetically proven FSHD1
3. Ability to participate in functional testing at the determination of the principal investigator. 
4. Sufficient muscle mass for muscle biopsy, as determined by examination and by MRI of limb muscles. 

Exclusion Criteria: 

1. History of bleeding disorder
2. Abnormalities of platelet levels, prothrombin time (PT)/INR, or partial thromboplastin time (PTT) that in the opinion of the PI would render the subject unsuitable for biopsy. This may be determined on screening blood test; subjects with abnormal results will be excluded from the study and referred to the hematology clinic for clinical follow-up. 
3. Inability to complete an MRI scan. 
4. Other medical or cognitive issues that, in the opinion of the examiner, preclude accurate functional assessment. 

Contact Information: 

Brittany Connor
Clinical Research Coordinator
Brittany.Connor@NationwideChildrens.org
(614) 355-2727

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 steroids
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

Principal Investigator: Dr. Linda Lowes

What’s the purpose of the study?

Researchers at Nationwide Children’s Hospital want to see if watching how a baby moves can identify whether he/she is likely to grow up to have movement problems. This could help doctors find these babies and get them treatment at a very young age.

Who can take part in the study?

Infants from birth to 6 months of age.

What will happen during the study?

You will:

• Be asked a few questions about your infant and his/her medical history
• Lay your infant under a camera so we can take a 4-minute recording

The study takes approximately 10 to 15 minutes.

Researchers will also review your child’s medical history over the first five years of their life. You may be contacted by phone, email or mail throughout this time if your child is no longer a patient at Nationwide Children’s.

For more information or to enroll your child, email NMDtrialinfo@NationwideChildrens.org or call (614) 722-6881.

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 3 clinic visits and 5 local blood draws over 6 months

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

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

Principal Investigator: Linda Lowes, PhD, PT

Sponsor: Sarepta Therapeutics, Coalition to Cure Calpain 3

Enrollment Status: Recruiting

Time Commitment: between 2 and 5 visits, depending on type of LGMD (the first is a two-day visit)

Purpose: The goal of this natural history study measure how hard it is for individuals with LGMD to do a variety of tasks. We would like to test you regardless of how strong you are right now. This is NOT a treatment trial but will help companies design trials to try new treatments in the future. We will enroll people with the following subtypes of LGMD: 2A Calpain, 2B Dysferlin, 2C Gamma Sarcoglycan, 2D Alpha Sarcoglycan, 2E Beta Sarcoglycan, 2F Delta Sacroglycan 2L ANO5, and 1D DNAJB6, 

Inclusion Criteria:

• Age between 4-65 at enrollment (depends on subtypes)
• A genetically confirmed mutation in CAPN3, DYSF, ANO5, DNAJB6, SGCA, SGCB, SGCD, or SGCG
• Have some noticeable weakness – even if it is very mild
• We would like both people who walk and those who use a wheelchair.

Exclusion Criteria: 

• Any other illness that would make it unsafe for you to be testing or make you perform differently
• History of a bleeding disorder, platelet count <50,000, current use of an anticoagulant
• Currently pregnant

Contact: 

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

Principal Investigator: Linda Lowes, PhD

Sponsor: ML Bio Solutions

Enrollment Status: Recruiting

Time Commitment: 4 visits in year 1 (first visit is a two-day visit)

Purpose: The goal of this natural history study measure how hard it is for individuals with LGMD2i to do a variety of tasks.  We would like to test you regardless of how strong you are right now. This is NOT a treatment trial, but will help companies design trials to try new treatments in the future.

Inclusion Criteria:

• Age between 10-65 at enrollment
• A genetically confirmed mutation in FKRP (LGMD 2i)
• Have some noticeable weakness – even if it is very mild
• We would like both people who walk and those who use a wheelchair.

Exclusion Criteria: 

• Any other illness that would make it unsafe for you to be testing or make you perform differently
• History of a bleeding disorder, platelet count <50,000, current use of an anticoagulant
• Currently pregnant

Reimbursement for travel costs and compensation for your time will be offered.

Contact: 

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

Principal Investigator: Linda Lowes, PhD

Enrollment Status: Recruiting

Time Commitment: Approximately 2 hours: 1 hour to answer written questionnaires and 1 hour to participate in an interview (conducted by video conference).

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.  

Purpose: The primary purposes of this study is to better understand the experiences of patients with DMD. The researchers will conduct interviews with parent and patient dyads and ask these same participants to answer several questionnaires that are normally used to assess functioning of patients with DMD. By comparing the information from the interviews with the answers to the questionnaires, the researchers hope to learn more about current measurements of function and how better to capture information about the changes and benefits that might result from future treatments. 

Inclusion Criteria:

Parents

1. Primary caregiver of a patient with a genetically confirmed DMD diagnosis
2. Willing and able to participate in a single 60-minute dyadic interview held via videoconference
3. Willing and able to complete a series of short questionnaires about the patient’s health
4. Can speak, read, write and understand English

Patients

1. At least 4 years old with a genetically confirmed DMD diagnosis
2. Willing and able to participate in a single 60-minute dyadic interview held via videoconference

Exclusion Criteria:

1. Any patient or parent currently participating in a clinical trial
2. Any patient currently receiving or who has previously received Exondys 51 or Vyondys 53.

Contact Information

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

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

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

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

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

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

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

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

Principal Investigator: Jerry R. Mendell, MD

Sponsor: Sarepta Therapeutics

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

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

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

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