Modulation of muscle regeneration by growth factors

描述（由申请人提供）：增强骨骼肌的生长和修复是肌肉萎缩症、肌肉减少症和废弃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 （Insulin-like growth factor I, IGF-I）通过调节蛋白质合成和卫星细胞的活动，一直被认为是促进肌肉生长和增强肌肉再生的关键因素之一。因为肌纤维是有丝分裂后的，修复必须依靠卫星细胞，一种靠近肌纤维的干细胞样细胞群，作为补充肌肉核含量的来源。卫星细胞通常处于静止状态，除非在肌肉生长过程中或损伤后被诸如igf - 1之类的信号触发。除了igf -1，一个新发现的肌肉损伤解决伙伴是基质金属蛋白酶13 （MMP-13）。我们发现，骨骼肌增加的igf -1产生也会驱动MMP-13的表达，因此这些蛋白质可能在修复过程中相互补充。目前，IGF-I治疗的现状是基于重组IGF-I的全身递送。然而，由于igf - 1在人体许多组织中是一种强有力的生长因子，并具有潜在的致癌风险，研究人员已经引入了限量的igf - 1。因此，临床试验产生的结果好坏参半，因为igf - 1对骨骼肌有益的能力受到两方面的限制：一是低水平的蛋白质施用，二是igf - 1通过循环向肌肉的有限分布。在我们早期的研究中（Barton- davis等人1998年；Barton等人2002年；Barton， 2006年），通过基因传递允许在肌肉特异性启动子下表达igf - 1来规避这一问题。我们现在试图在大型动物模型（狗）中定义最佳的igf - 1相关治疗，以病毒（AAV）载体递送。我们还试图用一种小分子治疗方法概括这种特异性病毒基因表达。建立了差异筛选，以发现可以调节骨骼肌细胞中igf - 1水平的化合物，但不能调节肝细胞中的igf - 1水平。这些分子是通过与新泽西一家小型生物技术公司（PTC Therapeutics）密切合作鉴定出来的，该公司开发了专有技术来筛选能够选择性调节目标mRNA翻译的小分子（筛选涉及靶向5‘和3’ utr）。

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.