Preclinical studies to validate the efficacy of novel mechanism-of-action small molecule inhibitors to treat Duchenne muscular dystrophy

验证新型作用机制小分子抑制剂治疗杜氏肌营养不良症疗效的临床前研究

• 批准号: 9908406
• 负责人: Harshini Neelakantan
• 金额: $ 25.21万
• 依托单位: RIDGELINE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908406
• 关键词: Address; Adolescent and Young Adult; Affect; Animal Model; Anti-inflammatory; Area Under Curve; Bioavailable; Biochemical; Bioenergetics; Caenorhabditis elegans; Cessation of life; Child; Clinical; Clinical Pathology; Clinical Trials; Deterioration; Disease Progression; Dose; Drug Delivery Systems; Drug Exposure; Drug Kinetics; Duchenne muscular dystrophy; Dystrophin; Effectiveness; Enzymes; FDA approved; Fibrosis; Functional disorder; Funding; Generations; Genes; Genetic; Glucocorticoids; Growth; Hand Strength; Human; In Vitro; Individual; Infant; Injectable; Injury; Lead; Longevity; Measures; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Mus; Muscle; Muscle Fibers; Muscle Mitochondria; Muscle Weakness; Muscle function; Muscle satellite cell; Muscular Atrophy; Muscular Dystrophies; Mutation; Myopathy; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Natural regeneration; Nicotinamide N-Methyltransferase; Oral; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Phenotype; Physical Function; Plasma; Quality of life; Research; Respiratory Diaphragm; Respiratory physiology; Route; S-Phase Fraction; Safety; Skeletal Muscle; Small Business Technology Transfer Research; Stress; Structure; Technology; Testing; Therapeutic; Therapeutic Effect; Time; United States National Institutes of Health; age related; aged; candidate validation; clinical development; deflazacort; effective intervention; efficacy study; efficacy testing; exon skipping; exposure route; feeding; heart function; improved; in vivo; inhibitor/antagonist; lead candidate; mdx mouse; metabolome; mouse model; muscle degeneration; muscle regeneration; muscle strength; muscular dystrophy mouse model; novel; novel therapeutics; overexpression; pre-clinical; preclinical development; preclinical study; predictive modeling; premature; programs; regenerative; repaired; respiratory; safety study; scale up; senescence; small molecule; small molecule inhibitor; small molecule therapeutics; treatment effect

Progressive muscle weakness and degeneration is a hallmark of Duchenne muscular dystrophy (DMD). In DMD patients, the lack of dystrophin reduces muscle fiber structural integrity, making muscles vulnerable to persistent injury and damage. Repairing these damaged muscles requires the continual activation of muscle stem cells (muSC), which leads to muSC dysfunction and senescence, and ultimately the muscle degeneration and weakness phenotype observed in DMD patients. Unfortunately, existing FDA approved drugs (eteplirsen, deflazacort) do not sufficiently improve muscle regeneration, and appear to provide only marginal improve- ments in muscle function and quality of life for DMD patients. Ridgeline Therapeutics has developed novel oral- ly-bioavailable small molecule NNMT (nicotinamide N-methyltransferase) inhibitors (e.g., RTL-72484) that reactivate dysfunctional and senescent muSC. While initially developed as a therapeutic to reverse age-related muscle degeneration, recent in vivo studies suggest the NNMT inhibitor RTL-72484 could improve muscle re- generation and function in DMD patients. This project will expand on our preliminary research and complete proof-of-concept studies to rigorously test the efficacy of RTL-72484 two complementary DMD mouse models. Overexpression of NNMT interferes with the NAD salvage pathway, muSC regenerative function, and cellu- lar metabolism (including mitochondrial bioenergetics). Skeletal muscles of DMD patients have greatly in- creased expression of NNMT, suggesting NNMT could be a vital contributing factor to muSC dysfunction and metabolic dysregulation observed in DMD patients. As a potential DMD treatment, RLT-72484 functions by se- lectively inhibiting NNMT, resulting in increased muSC activity, enhanced mitochondrial function, and ultimately improved muscle strength and function. These unique mechanisms-of-action makes RLT-72484 (and other NNMT inhibitors in our pipeline) distinct from the few DMD therapeutics that are FDA-approved or in early- stage clinical trials. This Phase I STTR project will build upon our encouraging in vivo DMD efficacy studies and test the effectiveness of RLT-72484 in more advanced and translationally-relevant murine models of DMD. The following two Aims will be completed to assess the potential of RLT-72484 to serve as an oral DMD drug. Aim 1 will complete an oral chow-admixed pharmacokinetic (PK) study to assess plasma profiles of RLT- 72484 and compare to systemic exposures observed via oral gavage administration of the drug. This PK study will validate the optimal drug delivery route for longitudinal efficacy studies in DMD mice. Aim 2 will complete in vivo dose-ranging efficacy studies using B10/mdx and D2/mdx mice models of DMD, evaluating muSC activity, mitochondrial function, diaphragm contractile function, and fibrosis ex-vivo, and in vivo functional endpoints (e.g., muscle strength, endurance, and grip strength). Following successful demonstration of the therapeutic effects of RTL-72484 in animal models, Ridgeline will rapidly advance RTL-72484 to clinical trials as a potential DMD treatment, since RLT-72484 is in GMP scale-up and GLP safety studies for a separate clinical indication.

进行性肌肉无力和退化是杜氏肌营养不良症 (DMD) 的标志。在 DMD 患者中，肌营养不良蛋白的缺乏会降低肌纤维结构的完整性，使肌肉容易受到 持续性伤害和损害。修复这些受损的肌肉需要不断激活肌肉 干细胞 (muSC)，导致 muSC 功能障碍和衰老，最终导致肌肉退化 以及在 DMD 患者中观察到的虚弱表型。不幸的是，现有 FDA 批准的药物（eteplirsen、 地夫可特）不能充分改善肌肉再生，并且似乎只能提供有限的改善- DMD 患者的肌肉功能和生活质量。 Ridgeline Therapeutics 开发了新型口服 生物可利用的小分子 NNMT（烟酰胺 N-甲基转移酶）抑制剂（例如 RTL-72484） 重新激活功能失调和衰老的 muSC。虽然最初是作为逆转年龄相关的治疗方法而开发的 肌肉退化，最近的体内研究表明 NNMT 抑制剂 RTL-72484 可以改善肌肉退化 DMD 患者的生成和功能。该项目将扩展我们的初步研究并完成 概念验证研究严格测试 RTL-72484 两种互补 DMD 小鼠模型的功效。 NNMT 的过度表达会干扰 NAD 挽救途径、muSC 再生功能和细胞 新陈代谢（包括线粒体生物能量学）。 DMD 患者的骨骼肌有很大的变化： NNMT 表达增加，表明 NNMT 可能是 muSC 功能障碍的重要影响因素 DMD 患者中观察到代谢失调。作为一种潜在的 DMD 治疗方法，RLT-72484 通过以下方式发挥作用： 选择性抑制 NNMT，导致 muSC 活性增加，线粒体功能增强，最终 改善肌肉力量和功能。这些独特的作用机制使得 RLT-72484（和其他 我们的产品线中的 NNMT 抑制剂）与 FDA 批准的或处于早期阶段的少数 DMD 疗法不同 阶段临床试验。该第一期 STTR 项目将建立在我们令人鼓舞的体内 DMD 功效研究的基础上 并测试 RLT-72484 在更先进且与转化相关的 DMD 小鼠模型中的有效性。 将完成以下两个目标，以评估 RLT-72484 作为口服 DMD 药物的潜力。 目标 1 将完成一项口服食物混合药代动力学 (PK) 研究，以评估 RLT- 的血浆特征 72484 并与通过口服强饲药物观察到的全身暴露进行比较。本次PK研究 将验证 DMD 小鼠纵向疗效研究的最佳药物递送途径。目标 2 将在 使用 DMD 的 B10/mdx 和 D2/mdx 小鼠模型进行体内剂量范围功效研究，评估 muSC 活性， 线粒体功能、膈肌收缩功能和纤维化离体和体内功能终点 （例如，肌肉力量、耐力和握力）。成功示范治疗效果后 RTL-72484在动物模型中的影响，Ridgeline将迅速将RTL-72484作为潜在的药物推进临床试验 DMD 治疗，因为 RLT-72484 正在针对单独的临床适应症进行 GMP 放大和 GLP 安全性研究。