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.

抽象的肌肉营养不良是严重的遗传疾病，其特征是肌肉浪费和逐渐丧失肌肉功能。目前，美国大约有25万个人受到某种形式的MD影响。尽管MD是由不同基因突变引起的，但肌肉病理患者的发展是共享的并通过脂肪和脂肪替换坏死肌纤维而表现为肌肉脂肪变性（FD）纤维化组织导致肌肉功能的丧失。肢体腰带肌肉营养不良2B（LGMD2B）影响肩膀和髋关节肌肉，导致患者的第二或第三个十年导致严重的功能障碍。由于糖皮质激素是糖皮质激素，目前尚无治愈或治疗的治疗方法 LGMD2B不建议某些类型的MD。基因编辑和替代疗法正在开发但是，面对有关效率和安全性的重大障碍。我们建议开发广告的生物治疗学” 专有剂ADA011（一种特定的TGF-β1/3抑制剂）进入抑制肌肉FD并保留的治疗 LGMD2B患者的肌肉功能。我们假设这可能有助于延迟症状的发作，缓解病理和疾病进展缓慢。此外，ADA011可以单独使用或在结合新兴的基因疗法，以防止患者现有FD的进展。我们已经确定了 ADA011作为潜在的，耐受性良好的TGF-β1/3抑制剂，效率抑制脂肪生成分化A 体外模型和抑制肌肉FD的体内小鼠诱导肌肉损伤模型。我们建议使用 ADA011在LGMD2B（Dysferlin-Null）的小鼠模型中抑制肌肉FD。在AIM 1中，我们将测试假设通过ADA011治疗的dysferlin-null小鼠在20周内的疾病进展与车辆控制相比。在AIM 2中，我们将确定肌肉愈合和功能是否通过 Dysferlin-Null小鼠急性损伤后ADA011治疗。 ADA011在LGMD2B的鼠标模型中的功效将有力地验证ADA011的治疗潜力并支持ADA011作为新颖的发展 LGMD2B患者的治疗。由于不存在LGMB2B患者抑制FD肌肉FD的治疗，因此 ADA011将是一类疗法，可以显着改善并延长健康和寿命 LGMD2B患者。