Preclinical Development of a Novel Therapeutic to Rejuvenate Aging Muscle Stem Cells and Enhance Muscle Strength and Function Post Hip Fracture

临床前开发一种新疗法，可以使衰老的肌肉干细胞恢复活力并增强髋部骨折后的肌肉强度和功能

• 批准号: 10696182
• 负责人: Harshini Neelakantan
• 金额: $ 124.3万
• 依托单位: RIDGELINE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10696182
• 关键词: Address; Adult; Age; Aging; American; Anabolism; Antibodies; Biological Markers; Canis familiaris; Chemicals; Chronic; Clinical; Clinical Trials; Complement; Data; Diet; Dose; Drug Kinetics; Drug Transport; Elderly; Energy Metabolism; Epigenetic Process; Event; Face; Fatal injury; Fracture; Functional disorder; GDF8 gene; Goals; Growth; Health; Health Care Costs; Hepatocyte; Hip Fractures; Hip region structure; Hospitalization; Human; Impairment; In Vitro; Independent Living; Individual; Injury; Investigational Drugs; Kilogram; Lead; Length of Stay; Link; Metabolic; Metabolism; Methionine; Modeling; Mus; Muscle; Muscle function; Muscle satellite cell; Muscular Atrophy; Myoblasts; Natural regeneration; Nicotinamide N-Methyltransferase; Operative Surgical Procedures; Oral; Orthopedic Surgery; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phenotype; Physical therapy; Physiological; Population; Positioning Attribute; Probability; Proteins; Protocols documentation; Quality of life; Rattus; Reaction; Recovery; Recovery of Function; Regenerative capacity; Regimen; Rehabilitation therapy; Rejuvenation; Risk; Rodent; Safety; Sampling; Skeletal Muscle; Skeletal Muscle Satellite Cells; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxic effect; Translating; Trauma; Traumatic injury; Up-Regulation; Validation; age related; age-related muscle loss; aged; bone fracture repair; cell age; clinical translation; clinically relevant; experience; fall injury; fall risk; falls; first-in-human; fracture risk; functional improvement; functional outcomes; high risk; improved; in vivo; indexing; inhibitor; injured; lead optimization; long term recovery; manufacture; manufacturing scale-up; metabolic abnormality assessment; metabolomics; mortality; muscle aging; muscle degeneration; muscle form; muscle regeneration; muscle strength; novel; novel therapeutics; older patient; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical development; preclinical study; predictive marker; reduced muscle strength; regeneration function; repaired; resistance exercise; satellite cell; scale up; selective androgen receptor modulator; skeletal muscle wasting; small molecule; small molecule therapeutics; standard of care; therapeutic development

Muscle-aging is defined by progressive declines in mass and strength that poses a high risk for falls, fatal injury, and trauma-related fractures among older Americans (age 60+). Each year, >30% of older adults suffer a fall, resulting in ~2.8 million traumatic fractures that significantly reduce mobility, independence, overall health, and quality of life for the elderly. Among fall-related injuries, hip fractures are the most prevalent and serious; the 300,000 elderly Americans hospitalized each year with hip fracture repairs face long-term post-surgery rehabilitation with a low probability of returning to independent living and a 1-year mortality rate that staggers around 10-30%. Dampened muscle strength predisposes to and predicts poor recovery among the elderly following hip fracture. Standard-of-care including resistance exercise and protein-rich diets only marginally improve muscle strength and functional outcomes post hip fracture. Attempts to improve muscle strength in elderly individuals using pharmacotherapies have not succeeded to date. To address this challenge, Ridgeline Therapeutics has developed first-in-class small molecule nicotinamide N-methyltransferase inhibitors (NNMTis) that reactivate aged muscle stem cells (muSCs). As skeletal muscle and muSCs age, they increasingly express NNMT that interferes with NAD biosynthesis and the downstream events that control muSC regenerative function and cellular energy metabolism. Thus, NNMT is a vital contributing factor to aging muSC dysfunction and associated declines in muscle strength. Since muSCs are fundamental to regeneration and repair, rejuvenation of aged muSCs (including using NNMTi) has proven useful to boost muscle regenerative capacity and improve muscle strength and function in aged mice. Ridgeline’s therapeutic development efforts have swiftly progressed from discovery, to lead optimization, mechanistic and preclinical proof-of-concept validations in clinically relevant aged muscle injury models. Treatment of aged, injured mice with the lead NNMTi RT-001 showed 2-fold increase in muSC activity and myofiber fusion index, 35-80% increase in muscle growth, and 70% increase in muscle strength. Robust efficacy and early safety index demonstration for RT-001 have de-risked and positioned it for late-stage preclinical and IND-enabling studies. Ridgeline is advancing RT-001 as a safe and effective small molecule therapeutic for clinical use in improving muscle strength and function among older adults following hip fracture surgical repairs. The objectives of this project directly aligns with this goal and focuses on completing necessary in vivo PK/PD studies to optimize oral dosing regimens, scale up synthesis of a 2 kilogram batch of RT-001, and non-GLP and GLP toxicity studies; accessory metabolism and clinically relevant biomarker assessments will be completed to complement and support IND filing and first-in-human clinical trials.

肌肉的衰老是由质量和力量的逐渐下降来定义的，质量和力量造成了跌倒，致命损伤和与创伤相关的老年人（60岁以上）的高风险。每年，> 30％的老年人遭受下降，导致约280万个创伤性分数可显着降低移动性，独立性，整体健康和老年人的生活质量。在与跌倒有关的伤害中，髋关节分数是最普遍，最严重的。每年有300,000名老式的美国人通过髋部骨折维修住院，面临长期手术后的康复，返回独立生活的可能性很小，而1年的死亡率则持续了约10-30％。在髋部骨折后，抑制肌肉力量易感并预测恢复不良。包括耐药性运动和富含蛋白质饮食在内的标准护理仅在髋部骨折后略微改善肌肉力量和功能结果。迄今为止，使用药物治疗的人尚未成功地改善老年人的肌肉力量。为了应对这一挑战，Ridgeline Therapeutics开发了第一类小分子烟酰胺N-甲基转移酶抑制剂（NNMTIS），该抑制剂（NNMTIS）重新激活了老化的肌肉干细胞（MUSC）。随着骨骼肌和MUSC的年龄，它们越来越表达NNMT，会干扰NAD生物合成和控制MUSC再生功能和细胞能量代谢的下游事件。这是NNMT是导致MUSC功能障碍衰老和肌肉力量下降的重要因素。由于MUSC是再生和修复的基础，因此被证明对衰老的MUSC（包括使用NNMTI）的恢复活力可用于提高肌肉再生能力并改善老年小鼠的肌肉力量和功能。 Ridgeline的治疗发展工作已从发现迅速发展到临床相关的老年肌肉损伤模型中的铅优化，机械和临床前概念验证验证。用铅NNMTI RT-001治疗老年人，受伤的小鼠的MUSC活性和肌纤维融合指数增加了2倍，肌肉生长增加了35-80％，肌肉力量增加了70％。 RT-001的强大效率和早期安全指数示范已脱离风险，并将其定位为后期临床前和辅助研究。 Ridgeline正在将RT-001作为一种安全有效的小分子治疗，用于改善髋部骨折手术维修后老年人的肌肉力量和功能。该项目的目标直接与该目标保持一致，并着重于完成必要的体内PK/PD研究以优化口服剂量方案，扩大2公斤RT-001的合成以及非GLP和GLP毒性研究；辅助代谢和临床相关的生物标志物评估将完成，以完成和支持IND归档和首次人类临床试验。