Oligodendrocyte-targeted adeno-associated virus gene therapy for Canavan disease in children: a phase 1/2 trial.

This open-label phase 1/2 clinical study uses a novel recombinant vector, rAAV-Olig001, with selective tropism for oligodendrocytes, to deliver gene therapy for Canavan disease (CD), a rare leukodystrophy characterized by defective aspartoacylase and elevated N-acetyl-aspartic acid (NAA) concentrations. A total of 8 participants received intracranial doses of 3.7 × 10 vector genomes (vg) of rAAV-Olig001-ASPA (MYR-101), with an interim analysis at 12 months. The primary objective was to assess the safety of intracranial dosing of MYR-101 in children with typical CD. Efficacy measures included Mullen Scales of Early Learning (MSEL), Gross Motor Function Measure (GMFM) and analysis of NAA, myelination, white matter and extracellular water content in the brain. The participants were White; 5 (62.5%) were male. Of the participants, 7 (87.5%) experienced ≥1 serious adverse event, none of which were considered MYR-101 related. All participants experienced ≥1 adverse event. All adverse events and serious adverse events resolved fully. Treatment reduced NAA concentrations in cerebrospinal fluid (P = 0.0008), increased myelination (P = 0.0137) and improved MSEL developmental outcomes (P = 0.0171). Thus, interim results suggest that gene therapy with MYR-101 is well tolerated and shows early effects in CD. While these findings are preliminary, reductions in NAA concentrations indicate ASPA expression and increases in myelination and imply successful targeting of oligodendrocytes. These results may support the development of similar gene therapy strategies for other demyelinating and metabolic brain disorders. ClinicalTrials.gov registration: NCT04833907 .