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.