Modulation of muscle regeneration by growth factors

生长因子调节肌肉再生

• 批准号: 8122854
• 负责人: Elisabeth R Barton
• 金额: $ 6.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8122854
• 关键词: Acute; Adolescent; Animal Model; Blood Circulation; Canis familiaris; Clinic; Clinical Trials; Complement; Complex; Development; Duchenne muscular dystrophy; Elderly; Evaluation; Gene Delivery; Gene Expression; Genetic; Goals; Growth; Growth Factor; Hepatocyte; Hereditary Disease; Human; Injury; Insulin-Like Growth Factor I; Lead; Messenger RNA; Mitotic; Muscle; Muscle Fibers; Muscle rehabilitation; Muscular Dystrophies; Musculoskeletal; Myoblasts; Myopathy; Myotonic Dystrophy; Natural regeneration; New Agents; New Jersey; Nuclear; Patients; Peptides; Phase; Phase I Clinical Trials; Phase I/II Trial; Population; Process; Production; Property; Protein Biosynthesis; Proteins; Recombinant IGF-I; Regenerative Medicine; Regulation; Research; Research Personnel; Resolution; Risk; Signal Transduction; Skeletal Muscle; Skin Tissue; Source; Specificity; Stem cells; Symptoms; Technology; Therapeutic; Tissue Engineering; Tissues; Toxic effect; Toxicology; Transgenes; Translational Research; Translations; Untranslated Regions; Up-Regulation; Viral; Viral Genes; Work; adeno-associated viral vector; age related; boys; collagenase 3; interest; mdx mouse; muscle regeneration; pre-clinical; prevent; promoter; repaired; sarcopenia; satellite cell; skeletal muscle growth; small molecule; therapeutic target

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.

描述（由申请人提供）：增强骨骼肌生长和修复是肌营养不良症、肌少症以及废用或急性损伤后肌肉康复的核心治疗目标。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活动来促进肌肉生长和增强肌肉再生的关键因素之一。由于肌肉纤维是有丝分裂后的，因此修复必须依赖于卫星细胞，这是一种靠近肌肉纤维的干细胞样群体，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 之外，新发现的解决肌肉损伤的伙伴是基质金属蛋白酶 13 (MMP-13)。我们发现骨骼肌 IGF-I 产生的增加也会驱动 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 疗法的当前状态建立在重组 IGF-I 的全身递送之上。然而，由于 IGF-I 是身体许多组织中的有效生长因子，并具有潜在的致癌风险，因此研究人员限制了 IGF-I 的用量。因此，临床试验产生了好坏参半的结果，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 等人，1998 年；Barton 等人，2002 年；Barton，2006 年），通过基因递送允许 IGF-I 在肌肉特异性启动子下表达，从而避免了这一点。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。我们还寻求用小分子治疗来概括这种特异性病毒基因表达。建立差异筛选是为了寻找可以调节骨骼肌细胞中IGF-I水平的化合物，但不能调节肝细胞中的IGF-I水平。此类分子是通过与新泽西州一家小型生物技术公司 (PTC Therapeutics) 密切合作而确定的，该公司开发了专有技术来筛选可以选择性调节目标 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（特别是肌营养不良症）相关的持续症状。因此，增强肌肉再生的疗法可以使患有遗传性疾病的患者、从肌肉损伤中恢复的患者以及老年人受益。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。