Laminin protein therapy for Congenital Muscular Dystrophy

描述（由申请人提供）：Merosin Deficient Congenital Muscular Dystrophy type 1A （MDC1A）是一种由LAMA2基因突变和层粘连蛋白-α2蛋白缺失引起的破坏性神经肌肉疾病。MDC1A患者从出生起就表现出严重的肌肉无力，只能坐在轮椅上，需要呼吸机辅助呼吸，预期寿命缩短。目前对MDC1A没有有效的治疗或治愈方法，除非很快发现治疗方法，否则所有受影响的儿童都将死于这种遗传性疾病。层粘连蛋白-α2是形成异三聚体层粘连蛋白-211 （α2， ß1, γ1）和层粘连蛋白-221 （α2， ß1, γ1）所必需的，它们是骨骼肌和心肌基板的主要成分。层粘连蛋白-111 （α2， ß1, γ1）是胚胎骨骼肌中主要的层粘连蛋白亚型，支持层粘连蛋白-α2缺陷肌的正常骨骼肌发育，但在成人骨骼肌中不存在。我们最近的研究表明，小鼠层粘连蛋白-111蛋白可以系统地递送到层粘连蛋白-α2缺陷小鼠的肌肉中，以防止肌肉病理，维持肌肉力量并显着延长预期寿命。这些发现表明，层粘连蛋白- 111对MDC1A的dyW-/-小鼠模型具有很强的治疗作用。在诊断时，患有MDC1A的儿童已经发生了明显的肌肉疾病，目前尚不清楚laminin-111蛋白治疗是否有效地预防疾病已经开始的疾病进展。本研究将研究laminin-111蛋白治疗是否可以预防发病后的疾病进展，确定重组人laminin-111是否可以预防肌肉疾病，并研究laminin-111蛋白治疗所赋予的保护机制。我们将验证层粘连蛋白-111蛋白可以在功能上替代层粘连蛋白- 211并作为MDC1A的有效治疗药物的假设。我们将在三个具体目标中检验这一假设。首先，我们将在MDC1A的dyW-/-小鼠模型中确定laminin-111是否能预防疾病发作后进一步的肌肉损伤，保持肌肉功能并提高存活率。其次，我们将确定转基因表达人laminin111、重组人laminin111或重组人laminin211是否能改善MDC1A的dyW-/-小鼠模型的临床前结果。最后，我们将确定laminin-111蛋白治疗的可扩展性，并确定小鼠和狗模型的药代动力学和药效学概况。这项研究的结果将为开发laminin-111蛋白疗法作为MDC1A的新疗法铺平道路。

DESCRIPTION (provided by applicant): Merosin Deficient Congenital Muscular Dystrophy type 1A (MDC1A) is a devastating neuromuscular disease caused by mutations in the LAMA2 gene and loss of laminin-α2 protein. MDC1A patients exhibit severe muscle weakness from birth, are confined to a wheelchair, require ventilator assistance to breathe and have reduced life expectancy. There is currently no effective treatment or cure for MDC1A and all affected children will die from this genetic disease unless treatments are soon discovered. Laminin-α2 is required for the formation of heterotrimeric laminin-211 (α2, ß1, γ1 ) and laminin-221 (α2, ß1, γ1) which are major constituents of skeletal and cardiac muscle basal lamina. Laminin-111 (α2, ß1, γ1 ) is the predominant laminin isoform in embryonic skeletal muscle and supports normal skeletal muscle development in laminin-α2 deficient muscle but is absent from adult skeletal muscle. We have recently shown that mouse laminin-111 protein can be systemically delivered to the muscle of laminin-α2 deficient mice to prevent muscle pathology, maintain muscle strength and dramatically increase life expectancy. These findings demonstrate that laminin- 111 is a highly potent therapeutic in the dyW-/- mouse model of MDC1A. At the time of diagnosis, children with MDC1A have developed significant muscle disease and it is unclear if laminin-111 protein therapy is effective at preventing disease progression after it has already started. This proposal will investigate if laminin-111 protein therapy can prevent disease progression after onset, determine if recombinant human laminin-111 can prevent muscle disease and investigate the mechanism of protection conferred by laminin-111 protein treatment. We will test the hypothesis that laminin-111 protein can functionally substitute for laminin- 211 and serve as an effective therapeutic for MDC1A. We will test this hypothesis in three Specific Aims. First we will determine if laminin-111 prevents further muscle damage after disease onset, preserves muscle function and improves survival in the dyW-/- mouse model of MDC1A. Second we will determine if transgenic expression of human laminin-111, recombinant human laminin-111 or recombinant human laminin-211 improves preclinical outcomes in the dyW-/- mouse model of MDC1A. Finally we will determine scalability of laminin-111 protein therapy and define the pharmacokinetic and pharmacodynamic profiles in mouse and dog models. Results from this study will pave the way towards developing laminin-111 protein therapy as a novel therapeutic for MDC1A.