Testing SARM1 as a Therapeutic Target in Multiple Forms of Charcot-Marie-Tooth Disease

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Charcot-Marie-Tooth disease (CMT) affects 1:2500 people and there are presently no approved treatments, presenting a large, unmet clinical need. The fact that mutations in nearly 100 genes can cause CMT complicates the development of therapeutics, because a single strategy is unlikely to apply to all subtypes of CMT. Nonetheless, since peripheral motor and sensory axon degeneration is a hallmark of virtually all forms of CMT, therapies aimed at protecting axons from degeneration may broadly apply to many or most forms of CMT. The SARM1 protein has been shown to be a key component of the cellular program of axon degeneration. Therefore, inhibiting SARM1 may be beneficial in CMT, although this has not yet been rigorously tested. Inhibiting SARM1 is indeed effective in preventing axon degeneration in a number of nerve insults, including injury, chemotherapy-induced neuropathy, and diabetic/metabolic neuropathy. Based on the axon protective actions of inhibiting SARM1, and the efficacy of SARM1 inhibition in other axonopathies, we hypothesize that inhibiting SARM1 may be a beneficial therapeutic strategy in multiple forms of CMT. We will test this hypothesis using mouse models of five disparate forms of CMT, including both axonal and demyelinating disease types. These mouse models include CMT2D/Gars, CMT2E/Nefl, CMT2S/Ighmbp2, CMT1X/Gjb1, and CMT4J/FIG4. In all cases, validated mouse models of these diseases exist and were created by or imported to The Jackson Laboratory. To inhibit SARM1, we will use a published AAV-delivered SARM1 dominant-negative construct, which simplifies dosing and mouse breeding. The efficiency of this approach will allow us to test the possible benefits of SARM1 inhibition in five models within the scope of this proposal. We will compare treated and untreated mice using established, clinically relevant outcome measures to determine if inhibiting SARM1 prevents, delays, or mitigates the neuropathy phenotype in these mouse models, including behavioral, physiological, and histological readouts. The efficacy of inhibiting SARM1 will be evaluated based on ages and outcomes optimized for each model. The successful completion of this project will help inform whether SARM1 inhibition may apply broadly across many forms of CMT, or whether only a subset of forms will respond. As SARM1 inhibitors are under development by a number of companies, these results have important implications for CMT patients, including patients with genetically undiagnosed forms of the disease who may hope to benefit from a broadly applicable approach.