Durable Global Correction of CNS and PNS and Lifespan Rescue in Murine Globoid Cell Leukodystrophy via AAV9-Mediated Monotherapy.
Journal
Cells
Journal Volume
14
Journal Issue
24
Start Page
Article Number : 1942
ISSN
2073-4409
Date Issued
2025-12-08
Author(s)
Lin, Dar-Shong
Ho, Che-Sheng
Huang, Yu-Wen
Lee, Tsung-Han
Huang, Zo-Darr
Wang, Tuan-Jen
Huang, Sung-Fu
Abstract
Globoid cell leukodystrophy (GLD) is a devastating lysosomal storage disorder caused by galactocerebrosidase (GALC) deficiency, leading to cytotoxic psychosine accumulation, broad neuroinflammation, dysfunction of autophagy and ubiquitin-proteasome system, progressive demyelination in both the central (CNS) and peripheral nervous systems (PNS), and premature death. Curative treatments are lacking, highlighting the urgent need for transformative approaches. Existing therapies have failed to achieve durable metabolic correction across neural compartments or sustained functional recovery. Here, we demonstrate that a single intracranial administration of high-titer AAV9-GALC targeting the thalamus and deep cerebellar nuclei achieves unprecedented and lifelong therapeutic efficacy in the Twitcher mouse model of GLD. This region-specific monotherapy achieved broad neuronal and glial transduction throughout the CNS and PNS, resulting in sustained supraphysiological GALC activity and complete normalization of psychosine levels. Treated mice exhibited preserved proteostasis, axonal architecture, and myelin integrity, inhibition of neuroinflammation, alongside restored motor function. Remarkably, treated mice attain lifespans approaching wild-type levels, far surpassing all previously reported interventions in this model, indicating a durable, possibly lifelong therapeutic effect. By achieving durable and comprehensive metabolic and structural correction across neural systems without repeated dosing, multi-route delivery, combinational therapy, hematopoietic stem cell transplantation, or high-dose systemic delivery, this study establishes CNS-directed AAV9 monotherapy as a clinically translatable and potentially lifelong therapeutic paradigm for GLD.
Subjects
AAV
GALC
autophagy
demyelination
gene therapy
globoid cell leukodystrophy
neuroinflammation
psychosine
Publisher
Multidisciplinary Digital Publishing Institute (MDPI)
Type
journal article