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

• 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
• 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

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.

项目概要/摘要 腓骨肌萎缩症 (CMT) 影响 1:2500 人，目前尚无批准的治疗方法， 提出了巨大的、未满足的临床需求。近 100 个基因突变可导致 CMT 使治疗方法的开发变得复杂，因为单一策略不太可能适用于所有亚型 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，旨在保护轴突免于退化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 可能对 CMT 有益，尽管这一点尚未得到证实。 经过严格测试。抑制 SARM1 确实可以有效预防多种神经的轴突变性 损伤，包括损伤、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 SARM1 抑制在其他轴突病中的功效，我们 假设抑制 SARM1 可能是多种形式的 CMT 的有益治疗策略。我们将 使用五种不同形式的 CMT 小鼠模型检验这一假设，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/FIG4。在所有情况下，这些疾病的经过验证的小鼠模型都存在并且被 由杰克逊实验室创建或导入。为了抑制 SARM1，我们将使用已发布的 AAV 交付的 SARM1 显性失活构建体，简化了给药和小鼠育种。这个的效率 该方法将使我们能够在本研究范围内的五个模型中测试 SARM1 抑制的可能好处 提议。我们将使用已确定的临床相关结果来比较治疗和未治疗的小鼠 确定抑制 SARM1 是否可以预防、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的功效 将根据每个模型优化的年龄和结果进行评估。本次活动的顺利完成 该项目将有助于了解 SARM1 抑制是否可以广泛应用于多种形式的 CMT，或者是否 只有一部分表单会做出响应。由于许多公司正在开发SARM1抑制剂， 这些结果对 CMT 患者具有重要意义，包括基因未确诊的患者 可能希望从广泛适用的方法中受益的疾病形式。