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Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse models
Kathryn H. Morelli, … , Scott Q. Harper, Robert W. Burgess
Kathryn H. Morelli, … , Scott Q. Harper, Robert W. Burgess
Published September 26, 2019
Citation Information: J Clin Invest. 2019;129(12):5568-5583. https://doi.org/10.1172/JCI130600.
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Research Article Genetics Neuroscience

Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse models

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Abstract

Gene therapy approaches are being deployed to treat recessive genetic disorders by restoring the expression of mutated genes. However, the feasibility of these approaches for dominantly inherited diseases — where treatment may require reduction in the expression of a toxic mutant protein resulting from a gain-of-function allele — is unclear. Here we show the efficacy of allele-specific RNAi as a potential therapy for Charcot-Marie-Tooth disease type 2D (CMT2D), caused by dominant mutations in glycyl-tRNA synthetase (GARS). A de novo mutation in GARS was identified in a patient with a severe peripheral neuropathy, and a mouse model precisely recreating the mutation was produced. These mice developed a neuropathy by 3–4 weeks of age, validating the pathogenicity of the mutation. RNAi sequences targeting mutant GARS mRNA, but not wild-type, were optimized and then packaged into AAV9 for in vivo delivery. This almost completely prevented the neuropathy in mice treated at birth. Delaying treatment until after disease onset showed modest benefit, though this effect decreased the longer treatment was delayed. These outcomes were reproduced in a second mouse model of CMT2D using a vector specifically targeting that allele. The effects were dose dependent, and persisted for at least 1 year. Our findings demonstrate the feasibility of AAV9-mediated allele-specific knockdown and provide proof of concept for gene therapy approaches for dominant neuromuscular diseases.

Authors

Kathryn H. Morelli, Laurie B. Griffin, Nettie K. Pyne, Lindsay M. Wallace, Allison M. Fowler, Stephanie N. Oprescu, Ryuichi Takase, Na Wei, Rebecca Meyer-Schuman, Dattatreya Mellacheruvu, Jacob O. Kitzman, Samuel G. Kocen, Timothy J. Hines, Emily L. Spaulding, James R. Lupski, Alexey Nesvizhskii, Pedro Mancias, Ian J. Butler, Xiang-Lei Yang, Ya-Ming Hou, Anthony Antonellis, Scott Q. Harper, Robert W. Burgess

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Figure 7

Long-term therapeutic effects of neonatal scAAV9.mi.P278KY treatment.

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Long-term therapeutic effects of neonatal scAAV9.mi.P278KY treatment.
(A...
(A and B) scAAV9.mi.P278KY-treated P278KY mice displayed increases in body weight (A) starting at 24 weeks after treatment and in grip strength (B) throughout the course of 1 year compared with vehicle control–treated P278KY mice. (C and D) When evaluated for primary signs of neuropathy at 1 year after treatment, treated P278KY mice exhibited greater MW/BW ratios (C) and faster NCVs (D). (E–G) scAAV9.mi.P278KY treatment could preserve all populations of axons in the motor branch of the femoral nerve at 1 year after treatment. Significance in A and B was determined by 1-way ANOVA with Tukey’s HSD post hoc comparisons. Significance in C, D, and F was determined by 2-way ANOVA with Tukey’s HSD post hoc comparisons. Significant changes in axon diameter (G) were determined with a Kolmogorov-Smirnov test. Mi.LacZ-treated Gars+/+, n = 3; scAAV9.mi.P278KY-treated Gars+/+, n = 3; mi.LacZ-treated GarsP278KY/+, n = 5; and scAAV9.mi.P278YK-treated GarsP278KY/+, n = 7. Values are mean ± SD.

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

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