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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.

有限的肌肉使用在老年人中很普遍（例如，损伤后制动、卧床休息），并且通常导致废用性肌肉萎缩，定义为肌肉质量、力量和功能的大量丧失[1- 3]。老年人的整体健康和功能独立性可能会迅速和逐步恶化，肌肉废用导致萎缩，并促进进一步肌肉废用的恶性循环，萎缩加剧。对抗骨骼肌萎缩的标准治疗包括物理治疗和锻炼[4]，但这些方法在老年人群中的成功有限[5]。虽然制药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。唯一获批的在美国，干预是针对与HIV/AIDS和恶病质相关的萎缩亚型[6]。由此可见，有迫切需要预防和逆转老年人废用性肌萎缩的新治疗方法。 Ridgeline Therapeutics正在开发变革性的小分子口服药物，以加速骨骼肌再生和修复在老年人。Ridgeline的临床候选药物RT-002正在完成临床前研究，第一次人体1期临床试验计划于2023年第四季度进行。RT-002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的关键酶，稳态[7]。抑制NNMT激活静止的、功能失调的肌肉干细胞，促进增强的老年小鼠的肌纤维生长和改善肌肉质量和力量[8]。SBIR第1阶段项目将扩展这些发现并测试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的恢复。目标1将确定RT-002治疗是否可以减轻损失在肌肉废用期间发生的肌肉质量和力量的变化。目标2将确定RT-002治疗是否可以提高石膏固定诱导的肌肉萎缩的恢复率，如通过肌肉质量测量的，在21天的肢体再活动中获得的力量和功能（即，后uncasting）时期相比，在肢体取出的第一天进行基线测量。本文提出的有效性研究将利用一个诊断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，并导致显著萎缩，在老年大鼠中表现为大量肌肉损失和后肢肌肉严重缺陷强度持续几天，即使在铸件拆除[10，11]。此外，后肢铸造是一个广泛的- 废用性肌萎缩的公认模型与人类肌萎缩的转化相关性病理学[9，12]。使用该模型对RT-002的有效性进行临床前验证将为快速将其作为一种新型药物推进临床开发，以加速废用后肌肉功能的恢复 in aging老化adults成人.