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

肌肉老化的定义是，在美国老年人(60岁以上)中，质量和力量的进行性下降是跌倒、致命伤害和创伤相关骨折的高风险。每年，30%的老年人跌倒，导致约280万人发生创伤性骨折，显著降低老年人的行动能力、独立性、整体健康和生活质量。在与跌倒相关的伤害中，髋部骨折是最常见和最严重的；每年因髋部骨折修复而住院的30万美国老年人面临着术后长期康复的问题，恢复独立生活的可能性很低，一年内的死亡率约为10%-30%。老年人髋部骨折后，肌肉力量减弱易患上并预示着康复不良。标准护理，包括抵抗运动和富含蛋白质的饮食，只能略微改善髋部骨折后的肌肉力量和功能结果。使用药物疗法改善老年人肌肉力量的尝试到目前为止还没有成功。为了应对这一挑战，Ridgeline Treeutics开发了一流的小分子烟酰胺N-甲基转移酶抑制剂(NNMTi)，可以重新激活老化的肌肉干细胞(MuSCs)。随着骨骼肌和MuSCs年龄的增长，它们越来越多地表达干扰NAD生物合成的NNMT，以及控制MUSC再生功能和细胞能量代谢的下游事件。因此，NNMT是导致衰老的MUSC功能障碍和相关的肌肉力量下降的重要因素。由于MuSCs是再生和修复的基础，对衰老的MuSCs进行年轻化(包括使用NNMTi)已被证明有助于提高老龄小鼠的肌肉再生能力，改善肌肉力量和功能。Ridgeline的治疗开发工作已经从发现迅速发展到在临床相关的老年肌肉损伤模型中领导优化、机械和临床前概念验证。使用领先的NNMTi RT-001治疗老年损伤小鼠，显示MUSC活性和肌纤维融合指数增加2倍，肌肉生长增加35-80%，肌肉力量增加70%。RT-001的强大疗效和早期安全指数证明降低了风险，并将其用于晚期临床前和IND使能研究。Ridgeline正在推进RT-001作为一种安全有效的小分子治疗药物，用于临床改善髋部骨折手术修复后老年人的肌肉力量和功能。该项目的目标直接与这一目标相一致，并专注于完成必要的体内PK/PD研究，以优化口服给药方案，扩大2公斤批次RT-001的合成，以及非GLP和GLP毒性研究；将完成辅助代谢和临床相关生物标记物评估，以补充和支持IND申报和首个人类临床试验。

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.