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

一种预防和逆转老年人骨骼肌萎缩的新型小分子口服疗法

基本信息

批准号：
10761425
负责人：
Harshini Neelakantan
金额：
$ 32.24万
依托单位：
RIDGELINE THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10761425
关键词：
Acceleration Adult Aging Animal Model Animals Area Arthralgia Atrophic Bed rest Body Weight Cachexia Clinic Clinical Deterioration Development Disuse Atrophy Dose Dual-Energy X-Ray Absorptiometry Elderly Energy Metabolism Enzymes Event Excision Exercise FBXO32 gene FRAP1 gene Failure Female Femur Flexor Foundations Gait speed Gastrocnemius Muscle Gene Expression Growth HIV/AIDS Health Hindlimb Hindlimb Suspension Homeostasis Human Hypertrophy Immobilization Injury Intervention Limb structure Lipids Measures Mediating Minerals Modeling Mus Muscle Muscle Fibers Muscle Mitochondria Muscle function Muscle satellite cell Muscular Atrophy Neuromuscular Junction Nicotinamide N-Methyltransferase Norway Oral Outcome Pathology Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Phase Phase I Clinical Trials Physical Exercise Physical therapy Plasma Population Randomized Rattus Rattus norvegicus Recovery Risk Schedule Skeletal Muscle Small Business Innovation Research Grant Technology Testing Therapeutic Torque United States Validation Weight Work aged biomarker panel bone clinical candidate cohort density dietary supplements drug candidate effectiveness testing efficacy study first-in-human functional independence gain of function improved inhibitor inhibitor therapy injury recovery male muscle form muscle regeneration muscle strength new therapeutic target novel novel therapeutics older patient pharmacodynamic biomarker pre-clinical preclinical study prevent protein expression repaired sedentary lifestyle sex side effect skeletal muscle wasting small molecule standard of care success tibialis anterior muscle treatment duration treatment group

项目摘要

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.

在老年人中，有限的肌肉使用量很大（例如伤害后固定，床休息），通常是导致由肌肉质量，力量和功能大量丧失所定义的废除诱导的肌肉萎缩[1- 3]。衰老成年人的整体健康和功能独立性可以迅速而逐渐恶化肌肉消失会导致萎缩，并促进进一步的肌肉废弃的恶性循环加剧萎缩。应对骨骼肌萎缩的护理标准治疗包括物理治疗和运动[4]，但是这些方法在老年人群中取得了有限的成功[5]。虽然是药物治疗肌肉损失的干预措施正在发育中，许多人具有不利的副作用。唯一的批准在美国的干预是与与艾滋病毒/艾滋病和恶病质有关的萎缩的亚型[6]。那是对新的治疗方法的临界需求，可预防和逆转衰老成年人的肌肉萎缩。 Ridgeline Therapeutics正在开发转化的小分子口服药物以加速骨骼肌肉老年人的再生和修复。 Ridgeline的临床候选RT-002正在完成临床前研究，预定于第四季度的第一阶段临床试验，计划于4’23。 RT-002的行动机制是抑制烟酰胺N-甲基转移酶（NNMT），这是一种维持细胞能量代谢和稳态[7]。 NNMT的抑制会激活静止，功能失调的肌肉细胞，促进增强肌肉纤维生长和改善老年小鼠的肌肉质量和力量[8]。这个SBIR 1阶段项目将扩展这些发现并检验RT-002可以防止诱发肌肉萎缩和肌肉消失后，促进更快的恢复速度。 AIM 1将确定RT-002治疗是否可以减轻损失在肌肉消失期间发生的肌肉质量和力量。 AIM 2将确定RT-002治疗是否可以通过肌肉质量测量，提高铸造固定诱导的肌肉萎缩的恢复速率在21天的肢体重新启动（即未播种后）期间，力量和功能与在肢体无腐蚀的第一天采取的基线措施。本文提出的效率研究将利用与翻译相关的单侧后肢铸造模型大鼠肌肉萎缩[9]。铸造固定后肢，防止局部肌肉使用，并导致在老鼠的大鼠中，大大的肌肉损失和严重的后肢肌肉不足证明了萎缩即使在铸造后持续几天的力量[10，11]。此外，后肢铸造是一个广泛的被解雇诱导的肌肉萎缩的接受模型，与人肌肉萎缩的转化相关病理[9，12]。使用此模型对RT-002对RT-002有效性的临床前验证将为快速奠定基础将其发展到诊所中，作为一种新型药物，以加速废弃后肌肉功能的恢复在衰老的成年人中。