A novel agent for preventing fatty degeneration of muscles in LGMD2B

摘要 肌营养不良是严重的遗传性疾病，其特征是肌肉萎缩和进行性肌萎缩。 肌肉功能在美国，目前约有25万人受到某种形式的MD的影响。 虽然MD是由不同基因的突变引起的，但患者发生的肌肉病变是共同的。 并通过脂肪替代坏死的肌肉纤维而表现为肌肉脂肪变性（FD）， 导致肌肉功能丧失的纤维化组织。肢带型肌营养不良2B（LGMD 2B）影响 肩部和臀部肌肉，并导致患者的第二或第三个十年的严重功能残疾。 目前还没有治愈或治疗LGMD 2B的方法，因为糖皮质激素是治疗LGMD 2B的标准治疗。 某些类型的MD不建议用于LGMD 2B。正在开发基因编辑和替代疗法 但在功效和安全性方面面临重大障碍。我们建议开发生物治疗药物 专利药物ADA 011，一种特异性TGF-β1/3抑制剂，用于抑制肌肉FD并保留 LGMD 2B患者的肌肉功能。我们假设这可能有助于延迟症状的发作， 改善病理并减缓疾病进展。此外，ADA 011可单独使用或 与新兴的基因疗法联合，以预防患者现有FD的进展。我们已经确定 ADA 011是一种有效的、耐受性良好的TGF-β1/3抑制剂，可有效抑制脂肪形成分化， 体外模型和在诱导的肌肉损伤的体内小鼠模型中抑制肌肉FD。我们建议使用 ADA 011在LGMD 2B小鼠模型（dysferlin-null）中抑制肌肉FD。在目标1中，我们将测试这一点 通过分析ADA 011治疗的dysferlin无效小鼠20周内的疾病进展假设 与车辆对照相比。在目标2中，我们将确定肌肉愈合和功能是否得到改善， 在dysferlin缺失小鼠中急性损伤后的ADA 011治疗。ADA 011在该LGMD 2B小鼠模型中的疗效 这将有力地验证ADA 011的治疗潜力，并支持ADA 011作为一种新的 治疗LGMD 2B患者。由于不存在抑制LGMB 2B患者肌肉FD的治疗剂， ADA 011将是一种一流的治疗药物，可以显着改善和延长患者的健康和寿命。 LGMD 2B患者。

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.