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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，受伤后固定，卧床休息）