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- Title
AAV9-mediated FIG4 delivery prolongs life span in Charcot-Marie-Tooth disease type 4J mouse model.
- Authors
Presa, Maximiliano; Bailey, Rachel M.; Davis, Crystal; Murphy, Tara; Cook, Jenn; Walls, Randy; Wilpan, Hannah; Bogdanik, Laurent; Lenk, Guy M.; Burgess, Robert W.; Gray, Steven J.; Lutz, Cathleen
- Abstract
Charcot-Marie-Tooth disease type 4J (CMT4J) is caused by recessive, loss-of-function mutations in FIG4, encoding a phosphoinositol(3,5)P2-phosphatase. CMT4J patients have both neuron loss and demyelination in the peripheral nervous system, with vacuolization indicative of endosome/lysosome trafficking defects. Although the disease is highly variable, the onset is often in childhood and FIG4 mutations can dramatically shorten life span. There is currently no treatment for CMT4J. Here, we present the results of preclinical studies testing a gene-therapy approach to restoring FIG4 expression. A mouse model of CMT4J, the Fig4-pale tremor (plt) allele, was dosed with a single-stranded adeno-associated virus serotype 9 (AAV9) to deliver a codon-optimized human FIG4 sequence. Untreated, Fig4plt/plt mice have a median survival of approximately 5 weeks. When treated with the AAV9-FIG4 vector at P1 or P4, mice survived at least 1 year, with largely normal gross motor performance and little sign of neuropathy by neurophysiological or histopathological evaluation. When mice were treated at P7 or P11, life span was still significantly prolonged and peripheral nerve function was improved, but rescue was less complete. No unanticipated adverse effects were observed. Therefore, AAV9-mediated delivery of FIG4 is a well-tolerated and efficacious strategy in a mouse model of CMT4J.
- Subjects
LABORATORY mice; CHARCOT-Marie-Tooth disease; LIFE spans; ANIMAL disease models; PERIPHERAL nervous system; PROTEINS; BIOLOGICAL models; RESEARCH; VIRUSES; GENETICS; ANIMAL experimentation; RESEARCH methodology; MEDICAL cooperation; EVALUATION research; COMPARATIVE studies; RESEARCH funding; LONGEVITY; MICE
- Publication
Journal of Clinical Investigation, 2021, Vol 131, Issue 11, p1
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI137159