A novel agent for preventing fatty degeneration of muscles in LGMD2B

一种预防 LGMD2B 肌肉脂肪变性的新型药物

基本信息

批准号：
10542523
负责人：
Monique Floer
金额：
$ 25万
依托单位：
ADVERTENT BIOTHERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-07 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10542523
关键词：
Acute Adipose tissue Affect Aftercare Age Agreement Animal Model Appearance Biological Biological Response Modifier Therapy Charcot-Marie-Tooth Disease Clinical DYSF gene Data Development Diagnosis Disease Disease Progression Face Family Fatty acid glycerol esters Fibrosis Genes Genetic Diseases Glucocorticoids Glycerol Goals Growth Factor Hand Strength Health Heart Hip region structure Histologic Histopathology Human Hydroxyproline In Situ Individual Infiltration Injections Injury Intramuscular Kidney Knockout Mice Lead Legal patent Licensing Limb-Girdle Muscular Dystrophies Liver Longevity Measures Michigan Modeling Mus Muscle Muscle Development Muscle Fibers Muscle function Muscular Atrophy Muscular Dystrophies Musculoskeletal System Mutant Strains Mice Mutation Myopathy Necrosis Neurodegenerative Disorders Outcome Pathology Patients Phase Preclinical Drug Development Publishing RNA Replacement Therapy Rodent Rotator Cuff Running Safety Serum Shoulder Signal Transduction Skeletal Muscle Small Business Innovation Research Grant Sporadic Inclusion Body Myopathy Symptoms System Testing Therapeutic Time Tissues Toxicology Transforming Growth Factor beta Universities achilles tendon commercial application commercialization comorbidity drug candidate exhaustion field study functional disability gene therapy healing healthspan improved improved functioning in vitro Model in vivo inhibitor manufacturability mouse model muscle degeneration muscle regeneration musculoskeletal injury novel novel therapeutics preservation prevent safety study standard of care targeted treatment tibialis anterior muscle

项目摘要

Abstract Muscular dystrophies are grave genetic disorders characterized by muscle wasting and progressive loss of muscle function. Approximately 250,000 individuals are currently affected by some form of MD in the US. Although MDs are caused by mutations in different genes, the muscle pathologies patients develop are shared and manifest as muscle fatty degeneration (FD) through replacement of necrotic muscle fibers by adipose and fibrotic tissue leading to loss of muscle function. Limb Girdle Muscular Dystrophy 2B (LGMD2B) affects shoulder and hip muscles, and results in severe functional disability by a patient's second or third decade. There is currently no cure or therapy for LGMD2B since glucocorticoids, which are the standard-of-care for some types of MD, are not advised for LGMD2B. Gene editing and replacement therapies are being developed but face significant hurdles concerning efficacy and safety. We propose to develop Advertent Biotherapeutics' proprietary agent ADA011, a specific TGF-β1/3 inhibitor, into a therapy that inhibits muscle FD and preserves muscle function in LGMD2B patients. We hypothesize that this could help delay the onset of symptoms, ameliorate pathologies, and slow disease progression. Moreover, ADA011 could be used alone or in combination with emerging gene therapies to prevent progression of existing FD in patients. We have identified ADA011 as a potent, well-tolerated TGF-β1/3 inhibitor with efficacy inhibiting adipogenic differentiation an in vitro model and inhibiting muscle FD in an in vivo mouse model of induced muscle injury. We propose to use ADA011 to inhibit muscle FD in a mouse model of LGMD2B (dysferlin-null). In Aim 1 we will test this hypothesis by analyzing disease progression over 20 weeks in dysferlin-null mice treated with ADA011 compared to vehicle control. In Aim 2 we will determine whether muscle healing and function are improved by ADA011 treatment after acute injury in dysferlin-null mice. Efficacy of ADA011 in this mouse model of LGMD2B would powerfully validate the therapeutic potential of ADA011 and support development of ADA011 as a novel therapy for LGMD2B patients. Since therapeutics that inhibit FD of muscles in LGMB2B patients do not exist, ADA011 would be a first-in-class therapeutic that could significantly improve and extend health and lifespan of LGMD2B patients.

抽象的肌营养不良症是一种严重的遗传性疾病，其特征是肌肉萎缩和肌力进行性丧失。目前，美国约有 250,000 人受到某种形式的 MD 的影响。尽管 MD 是由不同基因突变引起的，但患者出现的肌肉病变是相同的并表现为肌肉脂肪变性（FD），通过脂肪和脂肪替代坏死的肌纤维。纤维化组织导致肌肉功能丧失，导致肢带型肌营养不良症 2B (LGMD2B) 的影响。肩部和臀部肌肉，并导致患者在第二个或第三个十年时出现严重的功能障碍。由于糖皮质激素是 LGMD2B 的标准治疗方法，目前尚无治愈或治疗方法某些类型的 MD 不建议进行 LGMD2B 基因编辑和替代疗法。但我们建议开发 Advertent Biotherapeutics'，但在功效和安全性方面面临重大障碍。将专利药物 ADA011（一种特定的 TGF-β1/3 抑制剂）纳入抑制肌肉 FD 并保留肌肉功能的疗法中 LGMD2B 患者的肌肉功能我们勇敢地认为这可能有助于延迟症状的出现，此外，ADA011 可以单独使用或联合使用。我们已经确定与新兴基因疗法相结合可预防患者现有 FD 的进展。 ADA011 作为一种有效、耐受性良好的 TGF-β1/3 抑制剂，可有效抑制脂肪形成分化和我们建议在诱导肌肉损伤的体内小鼠模型中使用体外模型和抑制肌肉FD。 ADA011 在 LGMD2B（dysferlin 缺失）小鼠模型中抑制肌肉 FD 在目标 1 中，我们将对此进行测试。通过分析接受 ADA011 治疗的 Dysferlin 缺失小鼠 20 周内的疾病进展得出的假设与车辆控制相比，我们将确定肌肉愈合和功能是否得到改善： ADA011 对 Dysferlin 缺失小鼠急性损伤后的治疗效果。将有力地验证 ADA011 的治疗潜力并支持 ADA011 作为新型药物的开发由于不存在抑制 LGMB2B 患者肌肉 FD 的疗法， ADA011将是一种一流的治疗方法，可以显着改善和延长患者的健康和寿命 LGMD2B 患者。