A novel agent for preventing fatty degeneration of muscles in LGMD2B

摘要 肌营养不良是一种严重的遗传性疾病，以肌肉萎缩和进行性丧失为特征。 肌肉功能。在美国，目前大约有25万人受到某种形式的MD的影响。 尽管MDS是由不同基因的突变引起的，但患者患上的肌肉病理是相同的 并表现为肌肉脂肪变性(FD)，通过脂肪和脂肪取代坏死的肌肉纤维 纤维组织导致肌肉功能丧失。肢体肌营养不良症2B(LGMD2B)影响 肩部和臀部肌肉，并在患者第二或第三个十年导致严重的功能残疾。 目前还没有治愈或治疗LGMD2B的方法，因为糖皮质激素是治疗LGMD2B的标准药物 某些类型的MD不建议用于LGMD2B。基因编辑和替代疗法正在开发中 但在有效性和安全性方面面临着重大障碍。我们建议开发注意的生物疗法‘ 专有药物ADA011，一种特定的转化生长因子-β1/3抑制剂，用于抑制肌肉FD并保存 LGMD2B患者的肌肉功能。我们假设这有助于延缓症状的出现， 改善病理，延缓疾病进展。此外，ADA011可以单独使用，也可以在 与新兴的基因疗法相结合，以防止患者现有FD的进展。我们已经确定了 ADA011作为一种有效的、耐受性良好的转化生长因子-β1/3抑制剂抑制成脂细胞的分化和生长 诱导肌肉损伤的体外模型和体内抑制肌肉功能障碍的小鼠模型。我们建议使用 ADA011抑制LGMD2B小鼠模型中的肌肉FD(deferlin-ull)。在目标1中，我们将测试这一点 分析ADA011治疗的干扰素缺失小鼠20周疾病进展的假说 与车辆控制相比。在目标2中，我们将确定肌肉愈合和功能是否通过 ADA011对干扰素缺失小鼠急性损伤后的治疗。ADA011对LGMD2B小鼠模型的治疗作用 将有力地验证ADA011的治疗潜力，并支持ADA011作为一种新的 LGMD2B患者的治疗。由于不存在抑制LGMB2B患者肌肉FD的治疗方法， ADA011将是一种一流的治疗药物，可以显著改善和延长患者的健康和寿命 LGMD2B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.