Modulation of muscle regeneration by growth factors

描述（由申请人提供）：骨骼肌生长和修复的增强是肌营养不良症、肌肉减少症和废用或急性损伤后肌肉康复的中心治疗目标。胰岛素样生长因子I（IGF-I）长期以来被认为是通过调节蛋白质合成和卫星细胞作用促进肌肉生长和增强肌肉再生的关键因子之一。由于肌纤维是有丝分裂后的，修复必须依赖于卫星细胞，一种位于肌纤维附近的干细胞样群体，作为补充肌肉核含量的来源。卫星细胞通常是静止的，除非被肌肉生长期间或损伤后增加的IGF-I等信号触发。除了IGF-I，一个新发现的伙伴在肌肉损伤的决议是基质金属蛋白酶13（MMP-13）。我们发现，骨骼肌IGF-I的产生增加也会驱动MMP-13的表达，因此这些蛋白质可能在修复过程中相互补充。IGF-I治疗剂的当前状态建立在重组IGF-I的全身递送上。然而，由于IGF-I在身体的许多组织中是一种有效的生长因子，并具有潜在的致癌风险，因此研究人员已经引入了有限数量的IGF-I。因此，临床试验产生了混合的结果，因为IGF-I为骨骼肌提供任何益处的能力受到所施用的低水平蛋白质以及IGF-I通过循环向肌肉的有限分布的限制。在我们早期的工作中（Barton-Davis，et al 1998;巴顿et al，2002;巴顿，2006），通过基因递送允许在肌肉特异性启动子下表达IGF-I来规避这一点。我们现在寻求在大型动物模型（狗）中定义用于在病毒（AAV）载体中递送的最佳IGF-I相关治疗剂。我们还试图用小分子治疗剂来概括这种特异性病毒基因表达。建立差异筛选以寻找可以调节骨骼肌细胞中但不调节肝细胞中IGF-I水平的化合物。通过与一家小型新泽西生物技术公司（PTC Therapeutics）密切合作，已经鉴定了这样的分子，该公司开发了专有技术来筛选可以选择性调节靶mRNA翻译的小分子（筛选涉及靶向5'和3' UTR）。 公共卫生相关性：骨骼肌修复发生在急性损伤后，是与遗传性肌肉疾病相关的持续症状，特别是在肌营养不良症中。因此，增强肌肉再生的疗法可以使患有遗传疾病的患者，从肌肉损伤中恢复的患者和老年人受益。开发可以增强肌肉再生的新药物，并在动物模型中评估这些药物是转化为临床的关键步骤。

DESCRIPTION (provided by applicant): Enhancement of skeletal muscle growth and repair is a central therapeutic target for the muscular dystrophies, sarcopenia, and muscle rehabilitation after disuse or acute injury. Insulin-like growth factor I (IGF-I) has long been recognized as one of the critical factors for promoting muscle growth and enhancing muscle regeneration through its regulation of protein synthesis and of satellite cell actions. Because muscle fibers are post-mitotic, repair must rely on satellite cells, a stem cell-like population residing close to muscle fibers as a source for replenishing nuclear content of the muscle. Satellite cells are normally quiescent unless triggered by signals such as IGF-I that are increased during muscle growth or after damage. In addition to IGF-I, a newly identified partner in the resolution of muscle damage is matrix-metalloproteinase 13 (MMP-13). We have found that increased IGF-I production by skeletal muscle also drives MMP-13 expression, and so these proteins may complement each other in the repair process. The current status of IGF-I therapeutics is founded on systemic delivery of recombinant IGF-I. However, because IGF-I is a potent growth factor in many tissues of the body and poses a potential carcinogenic risk, investigators have introduced IGF-I in limiting amounts. Thus, clinical trials have produced mixed results because the ability for IGF-I to provide any benefit to skeletal muscle is constrained by both the low level of protein administered, as well as the limited distribution of IGF-I to the muscle by the circulation. In our earlier work (Barton-Davis, et al 1998; Barton et al, 2002; Barton, 2006), this was circumvented by gene delivery allowing expression of IGF-I under a muscle-specific promoter. We now seek to define in a large animal model (dog), the optimal IGF-I related therapeutic for delivery in a viral (AAV) vector). We also seek to recapitulate this specificity viral gene expression with a small molecule therapeutic. Differential screens were set up to find compounds that can modulate IGF-I levels in skeletal muscle cells, but not in hepatocytes. Such molecules have been identified by working closely with a small New Jersey biotech company (PTC Therapeutics) that has developed proprietary technology to screen for small molecules that can selectively modulate translation of target mRNA (screens involve targeting the 5' and 3' UTRs). PUBLIC HEALTH RELEVANCE: Skeletal muscle repair occurs after acute injury and is an ongoing symptom associated with genetic muscle disease, specifically in the muscular dystrophies. Therefore, the therapies that enhance muscle regeneration can benefit patients suffering from genetic disease, those recovering from muscle injury, and the elderly. Development of new agents that can enhance muscle regeneration, and evaluation of these agents in animal models is a critical step for translation to the clinic.