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.

老年人普遍存在肌肉使用受限的情况（例如受伤后固定、卧床休息），并且通常导致废用性肌肉萎缩，其定义为肌肉质量、力量和功能的大量损失[1- 3]. 老年人的整体健康状况和功能独立性可能会迅速、逐渐恶化。肌肉废用会导致萎缩，并促进进一步肌肉废用和随后的恶性循环对抗骨骼肌萎缩的标准治疗方法包括物理治疗。和运动[4]，但这些方法在老年人群中的成功有限[5]。治疗肌肉损失的干预措施正在开发中，其中许多都有不利的副作用。美国的干预措施是针对与艾滋病毒/艾滋病和恶病质相关的萎缩亚型[6]。迫切需要新的治疗方法来预防和逆转老年人废用性肌肉萎缩。 Ridgeline Therapeutics 正在开发变革性小分子口服药物以加速骨骼肌生长 Ridgeline 的临床候选药物 RT-002 正在完成临床前研究， RT-002 的首次人体 1 期临床试验计划于 2023 年第 4 季度进行，其作用机制是抑制。烟酰胺 N-甲基转移酶 (NNMT)，一种对于维持细胞能量代谢至关重要的酶抑制 NNMT 会激活静止的、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以及肌肉质量和力量的改善[8]。扩展这些发现并检验 RT-002 可以预防废用性肌肉萎缩的假设促进肌肉废用后更快恢复目标 1 将确定 RT-002 治疗是否可以减轻损失。目标 2 将确定 RT-002 治疗是否有效。提高石膏固定引起的肌肉萎缩的恢复率（通过肌肉质量测量），与之前相比，在 21 天的肢体再活动（即脱模后）期间获得的力量和功能在肢体拆石膏第一天采取的基线措施。本文提出的功效研究将利用平移相关的单侧后肢铸造模型大鼠的肌肉萎缩[9]。显着萎缩，在老年大鼠中表现为明显的肌肉损失和后肢肌肉的严重缺陷即使在拆除石膏后，强度仍能持续数天 [10, 11] 此外，后肢石膏是一种广泛使用的方法。废用性肌肉萎缩的公认模型与人类肌肉萎缩的转化相关性使用该模型对 RT-002 的功效进行临床前验证将为快速奠定基础。它作为一种新药开发到临床，可加速废用后肌肉功能的恢复在老年人中。