Medical Professional Publications

Gene Therapy for Sanfilippo Syndrome Shows Promise, Safety and Efficacy

Columbus, OH - October 2016

No treatment is currently available for mucopolysaccharidosis (MPS) III, a group of four rare, autosomal recessive neuropathic lysosomal storage diseases, also known as Sanfilippo syndrome. However, researchers at Nationwide Children’s Hospital have developed effective adeno-associated viral (AAV)-based gene therapy approaches, targeting the root cause of the disease, for the treatment of MPS IIIA and MPS IIIB.

An interdisciplinary translational research team has also been formed at Nationwide Children’s to bring these gene therapy approaches to clinical trials in patients. The team has recently published two studies in preparation.

The first, a toxicology study in Human Gene Therapy Clinical Development, demonstrates a generally safe and effective profile for systemic AAV gene therapy. The second, in Molecular Genetics and Metabolism, is a natural history of MPS IIIA and IIIB in 25 patients, designed to identify appropriate methods to measure outcomes of a gene therapy trial.

“Caused by a single gene defect, most of the children with this disease do not reach adulthood,” says Kevin Flanigan, MD, attending neurologist at Nationwide Children’s, principal investigator in the Center for Gene Therapy in The Research Institute, and co-author of the study. “This investigational gene therapy approach represents a new treatment paradigm for addressing this relentlessly progressing disease.”

“Importantly, our toxicology studies also identified the upper dosing limit of systemic AAV gene delivery for the treatment of MPS IIIB,” says Haiyan Fu, PhD, lead author of the study and principal investigator in the Center for Gene Therapy. “This will guide safe clinical application in humans.”

Douglas McCarty, PhD, principal investigator in the Center for Gene Therapy and study co-author, notes that the progressive neurodegeneration of MPS IIIB, which begins in early childhood, necessitates effective gene delivery to the brain.

“Our approach is to employ intravenous injection of an AAV serotype that crosses the blood-brain-barrier,” explains Dr. McCarty. “We have also done numerous studies in mice to determine how far into the disease progression we can still achieve possible therapeutic benefits.”

The team has recently received two investigational new drug (IND) approvals from the FDA for Phase 1/2 gene therapy clinical trials for patients with MPS IIIA (ongoing) and MPS IIIB (to be initiated), both at Nationwide Children’s.


Meadows AS, Duncan FJ, Camboni M, Waligura K, Montgomery CL, Zaraspe K, Naughton BJ, Bremer WG, Shiling C, Walker C, Bolon B, Flanigan K, McBride KL, McCarty DM, Fu H. A GLP-compliant toxicology and biodistribution study: systemic delivery of a rAAV9 vector for the treatment of mucopolysaccharidosis IIIB. Human Gene Therapy Clinical Development. 2015 Dec; 26: 228-242.

Truxal KV, Fu H, McCarty DM, McNally KA, Kunkler KL, Zumberge NA, Martin L, Aylward SC, Alfano LN, Berry KM, Lowes LP, Corridore M, McKee C, McBride KL, Flanigan KM. A prospective one-year natural history study of mucopolysaccharidosis types IIIA and IIIB: Implications for clinical trial design. Molecular Genetics and Metabolism. 2016 Aug 18. [Epub ahead of print]

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