Intracerebral gene therapy in children with metachromatic leukodystrophy: Results of a phase I/II trial

No treatment is available for symptomatic early-onset forms of metachromatic leukodystrophy (late infantile-LI; early juvenile-EJ MLD), a devastating lysosomal disease caused by defect in arylsulfatase A (ARSA) gene. We describe herein the results of a phase I-II clinical trial, using intracerebral administration of an adeno-associated viral vector serotype rh.10 coding for human ARSA enzyme (AAVrh.10-hARSA), over a 2-years follow-up. Four MLD children (aged between 9 months and 5 years ½, 3 LI and 1 EJ) received 1012 or 4x1012 vector genome of AAVrh.10-hARSA, at a pre-symptomatic (N = 2) or early-symptomatic (N = 2) stage of their disease, administered at 12 location sites in the white matter of the centrum semiovale. Patients received corticosteroids from D-1 to D + 10. All patients were alive at the last timepoint. Two patients were withdrawn from the study at M + 12 (parents’ decision). 36 AEs and 8 SAEs were reported. One SAE was attributed to the neurosurgical procedure (intracranial suffusion, that resolved spontaneously). One SAE (seizures at M + 8) was declared treatment-related by the sponsor. Vital parameters and standard biology were unremarkable. AAVrh.10-hARSA was detected in urine up to D + 2 and in blood up to M + 3. Anti-AAV neutralizing factors raised up to M + 12, then tended to stabilize or decrease. There was no evidence for cellular immune response against ARSA transgene. Hyper-T2 signals around the injection sites were detected from M + 3 onwards and remained stable thereafter, independently on the vector dose and without clinical impact. ARSA activity in CSF, undetectable before treatment, increased significantly after injection, reaching 20%-70% of control values at the last assessment, with a dose dependent effect, attesting for vector functionality. Despite long-lasting restauration of ARSA activity, symptomatic patients continued to deteriorate and presymptomatic patients developed MLD disease, that was not significantly different from the natural history of the disease. Reasons for this insufficient efficacy will be discussed.