AAV9-mediated FIG4 delivery prolongs life span in Charcot-Marie-Tooth disease type 4J mouse model

Area of Science:

• Neurology
• Genetics
• Molecular Biology

Background:

• Charcot-Marie-Tooth disease type 4J (CMT4J) is a rare, inherited peripheral neuropathy caused by loss-of-function mutations in the FIG4 gene.
• The disease leads to neuron loss, demyelination, and endosome-lysosome trafficking defects, often with childhood onset and reduced lifespan.
• Currently, no effective treatments exist for CMT4J.

Purpose of the Study:

• To evaluate the efficacy of gene therapy for CMT4J by restoring FIG4 expression.
• To assess the safety and tolerability of adeno-associated virus serotype 9 (AAV9)-mediated gene delivery in a CMT4J mouse model.

Main Methods:

• A preclinical study utilized a single-stranded AAV9 vector to deliver a codon-optimized human FIG4 sequence to a mouse model of CMT4J (Fig4-pale tremor allele).
• Mice were treated at different ages (postnatal day 1, 4, 7, and 11) to assess the impact of treatment timing.
• Outcomes were evaluated through survival rates, gross motor performance, neurophysiological assessments, and histopathological examinations.

Main Results:

• AAV9-FIG4 gene therapy significantly prolonged the lifespan of Fig4plt/plt mice, with median survival exceeding one year when treated early (P1 or P4).
• Early treatment resulted in largely normal motor function and minimal signs of neuropathy.
• Later treatment (P7 or P11) also extended survival and improved nerve function, though to a lesser extent.
• No adverse effects were observed, indicating good tolerability.

Conclusions:

• AAV9-mediated delivery of FIG4 is a safe and effective gene therapy strategy in a CMT4J mouse model.
• The timing of gene therapy administration influences the degree of therapeutic benefit.
• This approach holds potential as a future treatment for CMT4J patients.