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

测试 SARM1 作为多种形式腓骨肌萎缩症的治疗靶点

基本信息

批准号：
10526224
负责人：
Robert W Burgess
金额：
$ 17.31万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10526224
关键词：
Address Affect Age Axon Axonal Neuropathy Behavioral Breeding Charcot-Marie-Tooth Disease Clinical Collection Complement Data Demyelinating Diseases Demyelinations Development Disease Disease model Dominant-Negative Mutation Dose Drosophila genus Drug Targeting Functional disorder Gene Fusion Genes Genetic Glaucoma Hand Histologic Human Genome Inherited Injury Interleukin Receptor Knock-out Knockout Mice Length Metabolic Modeling Monoclonal Antibody R24 Motor Mus Muscular Atrophy Mutation Myelin NAD+ Nucleosidase Nerve Neural Conduction Neurodegenerative Disorders Neurons Neuropathy Nicotinamide Mononucleotide Outcome Outcome Measure Parkinson Disease Patients Peripheral Peripheral Nervous System Peripheral Nervous System Diseases Persons Pharmaceutical Preparations Pharmacology Phenotype Physiological Proteins Public Health Publishing Resources Schwann Cells Sensory Sterility Testing The Jackson Laboratory Therapeutic Viral Wallerian Degeneration Work axon injury axonal degeneration axonopathy base chemotherapy induced neuropathy clinical examination clinically relevant diabetic disorder subtype drug development foot gain of function genetic disorder diagnosis inhibitor loss of function mutation mouse model mutant preservation prevent programs response success therapeutic development therapeutic target translational approach virtual

项目摘要

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.

项目摘要/摘要 charcot-marie-tooth病（CMT）影响1：2500人，目前没有批准的治疗方法提出了巨大的未满足的临床需求。近100个基因的突变会导致CMT的事实使治疗剂的发展变得复杂，因为单一策略不太可能适用于所有亚型 CMT。但是，由于外围电机和感觉轴突变性几乎是所有形式的标志在CMT中，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 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可能对CMT有益，尽管这尚未严格测试。抑制SARM1确实可以有效预防许多神经的轴突变性侮辱，包括损伤，化学疗法诱导的神经病和糖尿病/代谢神经病。基于抑制SARM1的轴突保护作用，以及SARM1在其他轴突病中的功效，我们假设抑制SARM1可能是多种形式CMT的有益治疗策略。我们将使用五种不同形式的CMT的小鼠模型来检验此假设，包括轴突和脱髓鞘类型。这些鼠标模型包括CMT2D/GARS，CMT2E/NEFL，CMT2S/IGHMBP2， CMT1X/GJB1和CMT4J/FIG4。在所有情况下，都存在经过验证的这些疾病的鼠标模型，并且由杰克逊实验室创建或进口。为了抑制SARM1，我们将使用已发表的AAV交付 SARM1占主导地位的构建体，简化了剂量和小鼠的繁殖。这个效率方法将使我们能够在此范围内测试五个模型中SARM1抑制的可能益处提议。我们将使用已建立的临床相关结果比较经过治疗和未处理的小鼠确定抑制SARM1是否预防，延迟或减轻神经病表型的措施小鼠模型，包括行为，生理和组织学读数。抑制SARM1的功效将根据针对每个模型优化的年龄和结果进行评估。成功完成项目将有助于告知SARM1抑制是否可以在许多形式的CMT上广泛应用，或者是否可以只有一部分表格会响应。由于许多公司正在开发SARM1抑制剂，因此这些结果对CMT患者具有重要意义，包括遗传诊断的患者可能希望从广泛适用的方法中受益的疾病形式。