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

项目摘要/摘要 Charcot-Marie-Tooth病(CMT)影响1：2500人，目前还没有批准的治疗方法， 呈现出巨大的、未得到满足的临床需求。近100个基因的突变可导致巨细胞白血病 使治疗学的发展复杂化，因为单一的策略不太可能适用于所有亚型的 CMT。尽管如此，由于外周运动和感觉轴突变性几乎是所有形式的标志 对于CMT，旨在保护轴突免受变性的疗法可能广泛适用于许多或大多数形式的 CMT。Sarm1蛋白已被证明是轴突细胞程序的关键组成部分 退化。因此，抑制Sarm1在CMT中可能是有益的，尽管这还没有得到证实 经过严格的测试。抑制Sarm1确实有效地防止了一些神经的轴突变性 侮辱，包括受伤、化疗引起的神经病变和糖尿病/代谢性神经病变。基于 抑制Sarm1的轴突保护作用，以及抑制Sarm1在其他轴突病变中的疗效 假设抑制Sarm1对多种形式的CMT可能是一种有益的治疗策略。我们会 使用五种不同形式的CMT的小鼠模型来验证这一假设，包括轴突和 脱髓鞘疾病类型。这些小鼠模型包括CMT2D/Gars、CMT2E/NEFL、CMT2S/Ighmbp2、 CMT1X/Gjb1和CMT4J/图4。在所有情况下，这些疾病的经过验证的小鼠模型都存在并被 由杰克逊实验室创建或导入到杰克逊实验室。为了抑制Sarm1，我们将使用已发布的AAV交付的 Sarm1显性-负性结构，简化了给药和小鼠饲养。这样做的效率 方法将允许我们在以下范围内的五个模型中测试Sarm1抑制的可能益处 求婚。我们将使用已建立的临床相关结果来比较治疗和未治疗的小鼠 确定抑制Sarm1是否预防、延迟或减轻这些患者的神经病变表型的措施 小鼠模型，包括行为、生理和组织学读数。抑制Sarm1的疗效 将根据年龄和为每个模型优化的结果进行评估。成功地完成这项工作 该项目将帮助了解Sarm1抑制是否可广泛应用于多种形式的CMT，或者是否 只有表单的子集才会响应。由于多家公司正在开发Sarm1抑制剂， 这些结果对CMT患者，包括遗传未确诊的患者具有重要的意义。 他们可能希望从一种广泛适用的方法中受益。

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.