Guest Column | July 6, 2020

Early Data Demonstrate Strengths of Gene Therapy Approaches for Sanfilippo Syndrome

By Karen Bulaklak, Ph.D. ASGCT Communications Committee

Initial safety and efficacy data from two clinical trials evaluating gene therapies for Sanfilippo syndrome were presented at the ASGCT 23rd Annual Meeting. Sanfilippo syndrome, or mucopolysaccharidosis IIIA (MPS IIIA), is a rare lysosomal storage disease that manifests in young children at a prevalence of about 0.17-2.35 per 100,000 births. Early in the disease course, patients display delayed neurocognitive development, behavior and speech problems, and seizures, which is followed by progressive intellectual and motor decline. About 70% of patients do not live past the age of 18, and there is currently no approved treatment for this devastating disease.

MPS IIIA is caused by a deficiency in N-sulfoglucosamine sulfohydrolase (SGSH), which leads to accumulation of heparan sulfate (HS). Gene therapy strategies have focused on overexpression of SGSH to reduce levels of HS and mitigate symptoms. In his presentation, “Transpher A, an Open-Label, Multicenter, Single-Dose, Dose Escalation, Phase 1/2 Clinical Trial of Gene Transfer of ABO-102 in Sanfilippo Syndrome Type A (Mucopolysaccharidosis IIIA): Safety, Tolerability, Biopotency and Neurocognitive Data,” Dr. Kevin Flanigan from Nationwide Children’s Hospital focused on a potential treatment consisting of a self-complementary AAV vector carrying SGSH. In the 15 patients included thus far, the therapy was well-tolerated, with no infusion-related adverse events or drug-related serious adverse events within 15-45 months post-treatment. All drug-related AEs were transient and resolved. After a single injection with the AAV, a rapid, dose-dependent reduction of HS and markers of neuronal injury were observed in cerebrospinal fluid. Decreases in plasma HS were seen across all doses and a durable reduction in liver volume was noted when compared to a natural history study. Furthermore, the treatment appeared to preserve neurocognitive development, particularly in the youngest patients, supporting early intervention.

Dr. Brian Bigger described results from ongoing work at the University of Manchester in his talk, “Preliminary Outcomes of Haematopoietic Stem Cell Gene Therapy in a Patient with Mucopolysaccharidosis IIIA.” The therapy relies on the natural trafficking of monocytes to the brain and enzymatic expression by blood cells to cross-correct affected cells, which has been achieved in preclinical studies in mice. To summarize the approach, hematopoietic stem cells are extracted from the patient, transduced with a lentiviral vector to overexpress SGSH, and transplanted back into patients. In the one patient evaluated so far, no SAEs were reported. Increased enzyme expression was observed across several blood cell types, with plasma and CSF levels above normal. This was accompanied by reduction of HS in urine, plasma and CSF. Neurocognitive evaluation will be performed at 12 months post-procedure.

While the approaches differ, both strategies appear to have favorable safety profiles and initial efficacy outcomes in these Phase I/II trials. Such exciting developments may someday lead to a life-changing therapy for these young patients and their families.