Charcot-Marie-Tooth Disease (CMT) is a heterogeneous collection of inherited polyneuropathies generallyCharacterize dby progressive muscle weakness and loss of sensation in the extremities. This disorder, for which there is currently no curative treatment, is the most common inherited disorder of the peripheral nervous system, affecting 1:2,500 individuals. Over 80 loci in the human genome have been linked to CMT, indicating that diverse cellular pathways are involved in its etiology. Fortunately, some common pathological mechanisms arebeginning to emerge, as thirteen different autosomal dominant mutations in GARS (glycyl-tRNA synthetase) have been identified in patients with CMT Type 2D (CMT2D). Although the mechanisms through which mutant forms of GARS cause axon degeneration are unclear, data from humans, mice, and Drosophila are consistent with the expression of mutant GARS protein causing toxic gain-of-function effects in peripheral nerves. Thus, our central hypothesis is that the selective silencing of mutant GARS expression should be of therapeutic benefit for patients with CMT2D. In response, we have developed a gene therapy strategy that specifically reduces mutant Gars expression through allele-specific RNAi. Recent exciting preliminary data confirms that when administered at birth, RNAi targeting mutant-Gars significantly improves all neuropathy outcome measures in an established mouse model of CMT2D (GarsP278KY/+). The overall objective for this proposal is to complete three specific aims designed to use mutant-Gars targeting RNAi as a powerful tool to gain novel mechanistic insights underlying CMT2D and to optimize the therapeutic potential of our gene therapy strategy.
In Aim 1 we will assess the efficacy of Gars-targeting RNAi in the prevention of neuropathy when delivered directly into the nervous system compared to its systemic delivery in GarsP278KY/+ mice. This study will determine if the disease is primarily driven by a cell autonomous or non- autonomous mechanism and establish the optimal route of delivery for our gene therapy approach.
In Aim 2 we will assess the potential for mutant Gars-targeting RNAi to arrest neuropathy in adult GarsP278KY/+ mice. This study will help us understand how neuropathy begins and progresses, and will help determine if our gene therapy strategy can treat current patients with CMT2D. The objective of Aim 3 is to generate ?humanized? preclinical mouse models that have a CMT2D patient-associated mutation substituted into the mouse Gars gene. This work will provide an in vivo platform to test personalized therapeutic strategies on disease-relevant mutations in in vivo models with established phenotypic validity. This study is significant and innovative, as we will demonstrate critical preclinical proof-of-concept data to help accomplish our long-term goal of developing a gene therapy for patients with CMT2D. This will be the first effective treatment for CMT2D or any dominant form of CMT and will have broad translational impact as it has implications for other common neuromuscular disorders including Huntington?s disease and motor neuron disorders.

Public Health Relevance

Charcot-Marie-Tooth Disease (CMT) is the most common inherited disorder of the peripheral nervous system in the United States, but unfortunately, it is currently incurable. The goal of the project is to optimize the therapeutic potential of a novel gene therapy strategy for CMT type 2D (CMT2D), a dominantly inherited form of CMT, using mice that model human CMT2D. Successful completion of the project will yield requisite proof of-principle data for the first effective treatment for treatment of CMT2D or any dominantly inherited form of CMT, and will have further implications for other common neuromuscular disorders such as Huntington?s disease and motor neuron disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Nuckolls, Glen H
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Jackson Laboratory
Bar Harbor
United States
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Morelli, Kathryn H; Seburn, Kevin L; Schroeder, David G et al. (2017) Severity of Demyelinating and Axonal Neuropathy Mouse Models Is Modified by Genes Affecting Structure and Function of Peripheral Nodes. Cell Rep 18:3178-3191