LAUSR

We report safety (primary endpoint) and efficacy (secondary endpoint) of novel intracerebral gene therapy at 5.5 years of follow-up in children with Sanfilippo B. An uncontrolled phase 1/2 clinical trial was performed in 4 patients aged 20, 26, 30 and 53 months. Treatment consisted in 16 intra-cerebral and cerebellar deposits of a recombinant adeno-associated viral vector encoding human -N-acetylglucosaminidase (rAAV2/5-hNAGLU) plus immunosuppression. An intermediate report at 30 months was previously published. Thirthy treatment emergent adverse events were reported between 30 and 66 months after surgery, including 3 classified as severe with no serious drug reactions. At 5.5 years, NAGLU activity was persistently detected in lumbar CSF (18% of unaffected control level). Circulating T cells reacting against NAGLU peptides were present, indicating a lack of acquired tolerance. Patient 2, 3 and 4 showed progressive brain atrophy and a neurocognitive evolution that did not differ from untreated SanfilippoA/B children. Patient 1 enrolled at 20 months of age had a milder disease with normal brain imaging and a significantly better cognitive outcome than the three other patients and untreated patients, although not equivalent to normal children. After 5.5 years, the primary endpoint of this study was achieved with a good safety profile of the proposed treatment. We have also observed sustained enzyme production in the brain and absence of immunological tolerance. Cognitive benefit was not confirmed in the 3 oldest patients. Milder disease in the youngest patient support further investigations of adeno-associated-vector-mediated intracerebral gene therapy in Sanfilippo B.