Mucopolysaccharidosis type IIIB (MPS IIIB or Sanfilippo Type B) is a fatal lysosomal storage disease leading to neurocognitive deterioration in early childhood, usually before 5 years of age. It is caused by mutations in the NAGLU gene resulting in a defective enzyme which cannot degrade heparan sulfate efficiently leading to its accumulation and the disease manifestations. In the past enzyme replacement therapy has been investigated, including delivery directly to the brain, but this has not led to an improvement in symptoms. Preclinical gene therapy studies in rodents and dogs suggested that this approach may hold the potential for therapeutic benefit.
Tardieu et al. 2017 report here the results of 4 children treated with intracerebral injections of rAAV2/5 containing the NAGLU transgene in a phase 1/2 clinical trial performed in France. Patients displayed a severe phenotype and were aged 20, 26, 30 and 53 months at the time of treatment and were followed up for 30m months after. The procedure was well tolerated and no serious adverse drug reactions were seen. Patients received immunosuppression on the basis of previous canine work (Ellinwood et al. 2011) and concern over immune responses to the protein, a move which the authors feel improved the efficacy of the treatment.
Neurocognitive decline was improved in all four patients compared to the natural history of the disease with the youngest patient benefitting most; their cognitive function was close to that of an unaffected child at enzyme levels in the CSF 15-20% of that found in healthy children. These results are clearly promising and suggest that this approach may offer patients with an essentially untreatable condition a treatment option and longer term follow up will hopefully demonstrate a persistent effect. But as with many other severe genetic disorders, early treatment appears to give the best results. The authors propose a therapeutic window of before 2 years of age which could allow for either prevention of neurocognitive decline or halting disease progression.
Ellinwood, N. M., et al. (2011). “Safe, efficient, and reproducible gene therapy of the brain in the dog models of Sanfilippo and Hurler syndromes.” Mol Ther 19(2): 251-259.
Tardieu, M., et al. (2017). “Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial.” Lancet Neurol 16(9): 712-720.