A dose escalation and safety study of AAVrh10-mediated Schwann cell-targeted gene therapy for CMT1X

• DOI: 10.1016/j.neurot.2025.e00568
• Publication Date: 2025-03-06T21:20:29Z
• Authors: Melina Christou; Irene Sargiannidou; Revekka Papachara...; Jan Richter; Christina Tryfonos; Christina Christo...; Alexia Kagiava; Kleopas A. Kleopa
• Keywords: Schwann cell; Remyelination; Peripheral Nervous System

X-linked Charcot-Marie-Tooth disease (CMT1X) is an inherited demyelinating neuropathy caused by loss-of-function mutations in the GJB1 gene, encoding gap junction protein connexin32 (Cx32). Cx32 plays a critical role Schwann cell function and myelin formation peripheral nervous system. We have developed gene replacement therapeutic approach using humanized AAVrh10 vector construct expressing under control of cell-specific human zero (MPZ) promoter. Lumbar intrathecal injection increasing AAVrh10-hMPZ.GJB1 doses (low: 1 ​× ​1011 vg, standard: 2 vg high: ​1012 vg) into Gjb1-null mice resulted adequate, dose-dependent biodistribution anterior lumbar roots nerves, as well high rates expression standard- high-dose groups. Both standard provided significant benefit evaluated behavioural, electrophysiological morphological outcomes. Intrathecal delivery induced production anti-AAVrh10 antibodies at 6 weeks post-injection. However, no histopathological or inflammatory changes were observed neural tissues, besides mild increase numbers sciatic nerves treated with dose only. This study provides proof concept for clinically translatable AAVrh10-mediated therapy CMT1X.