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Adeno-associated virus gene therapy to the rescue for Charcot-Marie-Tooth disease type 4J
John Svaren
John Svaren
Published June 1, 2021
Citation Information: J Clin Invest. 2021;131(11):e149492. https://doi.org/10.1172/JCI149492.
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Commentary Article has an altmetric score of 3

Adeno-associated virus gene therapy to the rescue for Charcot-Marie-Tooth disease type 4J

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Abstract

The genetic peripheral neuropathy known as Charcot-Marie-Tooth disease type 4J (CMT4J) is caused by recessive mutations in the FIG4 gene. The transformational success of adeno-associated virus (AAV) gene therapy for spinal muscular atrophy has generated substantial interest in using this approach to create similar treatments for CMT. In this issue of the JCI, Presa et al. provide a preclinical demonstration of efficacy using AAV-directed gene therapy for CMT4J. The study showed a dramatic improvement in both survival and neuropathy symptoms in a severe mouse model of CMT4J after administration of AAV gene therapy at several time points. The authors’ approach advances the technique for delivering treatments to individuals with CMT, for which FDA-approved therapies have not yet come to the clinic.

Authors

John Svaren

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Figure 1

Loss of FIG4 depletes PI(3,5)P2 and PI(5)P and causes CMT neuropathy.

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Loss of FIG4 depletes PI(3,5)P2 and PI(5)P and causes CMT neuropathy.
(A...
(A) Although FIG4 is a lipid phosphatase that can convert PI(3,5)P2 to PI(3)P, it exists within a complex with the lipid 5 kinase (PIKFYVE) and VAC14. Deficiency of any of the subunits results in deficiency of PI(3,5)P2 and PI(5)P, which are required for lysosomal homeostasis. (B) The altered TRIPML1 channel function and impaired lysosomal fission likely contribute to the prominent vacuolation phenotype in CMT4J. Similarly, cultured embryonic fibroblasts from Fig4 null mice accumulate large, acidic vacuoles (photograph provided with permission by G. Lenk and M. Meisler).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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