A Novel Small Molecule Oral Therapeutic to Prevent and Reverse Skeletal Muscle Atrophy in Aging Adults

有限的肌肉使用在老年人中很普遍(例如，受伤后的固定、卧床休息)，通常 导致废用性肌肉萎缩，定义为肌肉质量、力量和功能的严重丧失[1- 3]。老年人的整体健康和功能独立性可能会迅速和逐渐恶化， 肌肉停用会导致萎缩，并促进进一步的肌肉停用和随后的恶性循环 更严重的萎缩。对抗骨骼肌萎缩的标准护理疗法包括物理疗法 和锻炼[4]，但这些方法在老年人群中的成功有限[5]。虽然是药品 治疗肌肉损失的干预措施正在开发中，许多都有不利的副作用。唯一被批准的 在美国，干预是针对与艾滋病毒/艾滋病和恶病质相关的亚型萎缩[6]。因此，有 迫切需要新的治疗方法来预防和逆转老年人因停用而导致的肌肉萎缩。 Ridgeline Treateutics正在开发变革性小分子口服药物以促进骨骼肌 老年成人的再生和修复。Ridgeline的临床候选RT-002正在完成临床前研究， 计划于2003年第四季度进行人类首个第一阶段临床试验。RT-002‘S的作用机制是抑制 烟酰胺N-甲基转移酶(NNMT)，一种维持细胞能量代谢和 内稳态[7]。抑制NNMT激活静止的、功能失调的肌肉干细胞，促进增强 老年小鼠的肌肉纤维生长和肌肉质量和力量的改善[8]。该SBIR第一阶段项目将 扩展这些发现并检验RT-002可以防止废用引起的肌肉萎缩和 促进肌肉停用后更快的恢复。目标1将确定RT-002治疗是否可以减少损失 在肌肉停用期间发生的肌肉质量和力量的变化。AIM 2将确定RT-002治疗是否可以 提高石膏固定引起的肌肉萎缩的恢复率，以肌肉质量衡量， 在21天的肢体再动化(即，去石膏后)期间获得的力量和功能 断肢第一天所采取的基线措施。 本文提出的有效性研究将利用与翻译相关的单侧后肢铸型模型。 对大鼠肌肉萎缩的研究[9]。石膏固定后肢，防止局部肌肉的使用，并导致 显著萎缩，在老年大鼠中表现为大量肌肉丧失和后肢肌肉严重缺陷 即使在去除石膏后仍能持续数天的强度[10，11]。此外，后肢铸型是一种广泛的- 公认的废用性肌萎缩模型与人类肌肉萎缩的翻译相关性 病理学[9，12]。利用该模型对RT-002‘S的疗效进行临床前验证将为快速 作为促进停用后肌肉功能恢复的新药，推动其临床开发 在年迈的成年人中。

Limited muscle use is widespread in older adults (e.g., post-injury immobilization, bed rest) and typically leads to disuse-induced muscular atrophy defined by substantial loss of muscle mass, strength, and function [1- 3]. The overall health and functional independence of aging adults can rapidly and progressively deteriorate as muscle disuse causes atrophy and promotes a vicious cycle of further muscle disuse and subsequent exacerbated atrophy. Standard-of-care treatments to counter skeletal muscle atrophy include physical therapy and exercise [4], but these approaches have limited success in elderly populations [5]. Although pharmaceutical interventions to treat muscle loss are in development, many have unfavorable side effects. The only approved intervention in the United States is for subtypes of atrophy related to HIV/AIDS and cachexia [6]. Thus, there is a critical need for novel treatments that prevent and reverse disuse-induced muscular atrophy in aging adults. Ridgeline Therapeutics is developing transformative small-molecule oral drugs to accelerate skeletal muscle regeneration and repair in aging adults. Ridgeline’s clinical candidate RT-002 is completing preclinical studies, with first-in-human Phase 1 clinical trials scheduled for Q4’23. RT-002’s mechanism-of-action is to inhibit nicotinamide N-methyltransferase (NNMT), an enzyme critical for maintaining cellular energy metabolism and homeostasis [7]. Inhibition of NNMT activates quiescent, dysfunctional muscle stem cells, promoting enhanced muscle fiber growth and improved muscle mass and strength in aged mice [8]. This SBIR Phase 1 project will extend these findings and test the hypothesis that RT-002 can prevent disuse-induced muscle atrophy and promote faster recovery following muscle disuse. Aim 1 will determine if RT-002 treatment can mitigate the loss of muscle mass and strength that occurs during muscle disuse. Aim 2 will determine if RT-002 treatment can improve the rate of recovery from cast immobilization-induced muscle atrophy, as measured by muscle mass, strength, and function gained over a 21-day limb remobilization (i.e., post-uncasting) period compared to the baseline measures taken on the first day of limb uncasting. The efficacy studies proposed herein will utilize a translationally-relevant unilateral hindlimb casting model of muscle atrophy in rats [9]. Casting immobilizes the hindlimb, prevents localized muscle use, and results in significant atrophy, evidenced in aged rats by substantial muscle loss and severe deficits in hindlimb muscle strength that last for several days even after cast removal [10, 11]. Furthermore, hindlimb casting is a widely- accepted model for disuse-induced muscular atrophy with translational relevance to human muscle atrophy pathologies [9, 12]. Preclinical validation of RT-002’s efficacy using this model will lay the foundation to rapidly advance its development into the clinic as a novel drug to accelerate recovery of muscle function following disuse in aging adults.