Laminin protein therapy for Congenital Muscular Dystrophy

层粘连蛋白治疗先天性肌营养不良症

• 批准号: 8697998
• 负责人: DEAN J. BURKIN
• 金额: $ 31.57万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-23 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697998
• 关键词: Address; Adult; Affect; Aftercare; Animals; Apoptosis; Architecture; Basal lamina; Biological Assay; Birth; Breathing; Caliber; Canis familiaris; Cardiac; Cell Adhesion; Cells; Cessation of life; Child; Clinical Trials; Diagnosis; Disease Progression; Drug Kinetics; Echocardiography; Embryo; Enzyme-Linked Immunosorbent Assay; Exhibits; Extracellular Matrix; Future; Genes; Half-Life; Hereditary Disease; Human; Imaging technology; Immunoprecipitation; In Vitro; Indium-111; Inflammation; Label; Laminin; Life Expectancy; MDC1A; Mass Spectrum Analysis; Measures; Merosin; Modeling; Mus; Muscle; Muscle Cells; Muscle Development; Muscle Weakness; Muscle function; Mutation; Myocardium; Myopathy; Neuromuscular Diseases; Neuromuscular Junction; Onset of illness; Outcome; Pathology; Patients; Pharmacodynamics; Property; Protein Isoforms; Proteins; Recombinants; Respiratory Failure; Respiratory Muscles; Respiratory physiology; Serum; Skeletal Muscle; System; Testing; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Translating; Ventilator; Western Blotting; Wheelchairs; Whole Body Plethysmography; congenital muscular dystrophy; disease-causing mutation; effective therapy; functional outcomes; grasp; improved; in vivo; laminin-1; mouse model; muscle strength; novel therapeutics; overexpression; pre-clinical; premature; prevent; public health relevance; repaired

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-?2 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-?2 is required for the formation of heterotrimeric laminin-211 (?2, ?1, ?1) and laminin-221 (?2, ?1, ?1) which are major constituents of skeletal and cardiac muscle basal lamina. Laminin-111 (?2, ?1, ?1) is the predominant laminin isoform in embryonic skeletal muscle and supports normal skeletal muscle development in laminin-?2 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-?2deficient 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.

描述（由申请人提供）：Merosin 缺陷型先天性肌营养不良症 1A 型（MDC1A）是一种毁灭性的神经肌肉疾病，由 LAMA2 基因突变和层粘连蛋白-α2 蛋白缺失引起。 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，并且预期寿命缩短。目前尚无有效的治疗方法或治愈 MDC1A 的方法，除非尽快找到治疗方法，否则所有受影响的儿童都将死于这种遗传病。层粘连蛋白-α2是形成异三聚体层粘连蛋白-211（α2、β1、β1）和层粘连蛋白-221（β2、β1、β1）所必需的，它们是骨骼和心肌基底层的主要成分。 Laminin-111 (?2、?1、?1) 是胚胎骨骼肌中主要的层粘连蛋白亚型，支持层粘连蛋白-?2 缺陷肌肉中的正常骨骼肌发育，但在成年骨骼肌中不存在。我们最近发现，小鼠层粘连蛋白-111 蛋白可以系统性地输送到层粘连蛋白-β2 缺陷小鼠的肌肉中，以预防肌肉病理、维持肌肉力量并显着提高预期寿命。这些发现表明，laminin-111 在 dyW-/- MDC1A 小鼠模型中是一种高效的治疗剂。在诊断时，患有 MDC1A 的儿童已出现严重的肌肉疾病，目前尚不清楚层粘连蛋白 111 蛋白治疗在疾病开始后是否能有效预防疾病进展。该提案将研究层粘连蛋白 111 蛋白治疗是否可以预防发病后疾病进展，确定重组人层粘连蛋白 111 是否可以预防肌肉疾病，并研究层粘连蛋白 111 蛋白治疗所赋予的保护机制。我们将测试层粘连蛋白 111 蛋白可以在功能上替代层粘连蛋白 211 并作为 MDC1A 的有效治疗剂的假设。我们将在三个具体目标中检验这一假设。首先，我们将确定 laminin-111 是否可以防止疾病发作后进一步的肌肉损伤、保留肌肉功能并提高 MDC1A dyW-/- 小鼠模型的存活率。其次，我们将确定人层粘连蛋白 111、重组人层粘连蛋白 111 或重组人层粘连蛋白 211 的转基因表达是否可以改善 MDC1A dyW-/- 小鼠模型的临床前结果。最后，我们将确定层粘连蛋白 111 蛋白治疗的可扩展性，并定义小鼠和狗模型中的药代动力学和药效学特征。这项研究的结果将为开发层粘连蛋白 111 蛋白疗法作为 MDC1A 的新型疗法铺平道路。