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.

肌肉老化的定义是质量和力量逐渐下降，这给美国老年人（60 岁以上）带来跌倒、致命伤害和创伤相关骨折的高风险。每年，超过 30% 的老年人遭受跌倒。造成约 280 万人发生创伤性骨折，严重降低了老年人的活动能力、独立性、整体健康状况和生活质量。在与跌倒相关的伤害中，髋部骨折是最常见和最严重的，每年有 30 万名美国老年人因跌倒而住院。髋部骨折修复面临长期的术后康复，恢复独立生活的可能性很低，一年死亡率约为 10-30%。髋部骨折后老年人的肌肉力量减弱容易导致恢复不良。迄今为止，包括抗阻运动和富含蛋白质的饮食在内的标准护理只能略微改善髋部骨折后的肌肉力量和功能结果，但迄今为止尚未成功解决这一问题。为了应对这一挑战，Ridgeline Therapeutics 开发了一流的小分子烟酰胺 N-甲基转移酶抑制剂 (NNMTis)，可以重新激活衰老的肌肉干细胞 (muSC)。随着骨骼肌和 muSC 的衰老，它们会越来越多地表达 NNMT，从而干扰 NAD 生物合成及其下游。因此，NNMT 是导致 muSC 功能障碍和相关肌肉力量下降的重要因素。 muSC 是再生和修复的基础，衰老 muSC 的复兴（包括使用 NNMTi）已被证明有助于增强衰老小鼠的肌肉再生能力并改善肌肉力量和功能。 Ridgeline 的治疗开发工作从发现到领先优化和机制迅速取得进展。在临床相关的老年肌肉损伤模型中进行临床前概念验证，用先导 NNMTi RT-001 治疗老年受伤小鼠，结果显示 muSC 活性增加了 2 倍。 RT-001 的肌纤维融合指数、肌肉生长增加 35-80% 以及肌肉力量增加 70% 的强大功效和早期安全性指数证明已经降低了风险，并将其用于后期临床前和 IND 支持研究。 Ridgeline 正在将 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的老年人的肌肉力量和功能。该项目的目标与这一目标直接一致，并重点关注。完成体内 PK/PD 研究以优化口服给药方案、扩大 2 公斤批量 RT-001 的合成以及非 GLP 和 GLP 毒性研究是必要的；将完成辅助代谢和临床相关生物标志物评估，以补充和支持IND 申请和首次人体临床试验。