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.

进行性肌肉无力和变性是Duchenne肌肉营养不良（DMD）的标志。在 DMD患者，缺乏肌营养不良蛋白会降低肌肉纤维结构完整性，使肌肉容易受到伤害 持续的伤害和损害。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，最终导致肌肉变性 DMD患者观察到的无力表型。不幸的是，现有的FDA批准了药物（Eteplirsen， flazacort）不能充分改善肌肉再生，并且似乎只提供边缘改善 - DMD患者的肌肉功能和生活质量。 Ridgeline Therapeutics开发了新颖的口腔 Ly-bioavailable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MUSC。虽然最初是作为一种治疗性而开发的，以逆转与年龄有关 肌肉变性，最近的体内研究表明，NNMT抑制剂RTL-72484可以改善肌肉的重新 DMD患者的产生和功能。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的过表达会干扰NAD打捞途径，MUSC再生功能和Cellu- LAR代谢（包括线粒体生物能学）。 DMD患者的骨骼肌有很大的内在 NNMT的表达不足，表明NNMT可能是导致MUSC功能障碍的重要因素 DMD患者观察到代谢失调。作为潜在的DMD治疗，RLT-72484通过se-功能 分别抑制NNMT，导致MUSC活性增加，线粒体功能增强，并最终 改善肌肉力量和功能。这些独特的作用机制使RLT-72484（以及其他 我们的管道中的NNMT抑制剂与少数FDA批准或早期的DMD治疗剂不同 阶段临床试验。 I阶段I STTR项目将基于我们令人鼓舞的体内DMD功效研究 并测试RLT-72484在更高级和翻译的DMD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。 AIM 1将完成一项口服Chow Admixed药代动力学（PK）研究，以评估RLT-的血浆谱。 72484并与通过口服施用该药物观察到的全身性暴露相比。这项PK研究 将验证DMD小鼠纵向疗效研究的最佳药物输送途径。 AIM 2将完成 使用B10/MDX和D2/MDX小鼠DMD的体内剂量范围疗效研究，评估MUSC活性， 线粒体功能，隔膜收缩功能和纤维化函数和体内功能终终点 （例如，肌肉力量，耐力和握力）。成功地展示了治疗性 RTL-72484在动物模型中的影响，Ridgeline将迅速将RTL-72484迅速发展为临床试验，以此作为潜在的 DMD处理，因为RLT-72484在GMP缩放和GLP安全研究中进行单独的临床指示。