Leupeptin in a Canine Model of Duchenne Muscular Dystrophy

杜氏肌营养不良犬模型中的亮肽素

• 批准号: 7280088
• 负责人: Martin K Childers
• 金额: $ 16.6万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7280088
• 关键词: Leupeptin; Canine; Model; Duchenne; Muscular

DESCRIPTION (provided by applicant): This study seeks to determine efficacy of the calpain inhibitor, leupeptin, in the treatment of Duchenne muscular dystrophy (DMD) using a canine model. Data indicate that calpains play an important role in the pathogenesis of DMD. Accordingly, calpain inhibition may provide therapeutic benefit to patients. Our preliminary study in young dogs with canine muscular dystrophy suggests clinical benefit from oral leupeptin. We intent to extend these experiments using functional measures to assess leupeptin's potential as a treatment modality for humans with DMD. The specific aims are to: Specific Aim #1a: Evaluate efficacy of oral leupeptin (30mg/kg daily from 1-3 months of age) on muscle function as assessed by maximal isometric force in GRMD dogs. Specific Aim #1b: Evaluate efficacy of oral leupeptin (30mg/kg daily, 1- 3 months of age) on clinical disease progression as measured by tarsal joint angles in GRMD dogs. Specific Aim #2: Evaluate efficacy of oral leupeptin (SOmg/kg daily from 1- 3 months of age) on muscle damage and necrosis in a canine model of DMD as assessed by contraction-induced force deficit and histologic evaluation of muscle biopsies Specific Aim #3: Evaluate safety of daily oral leupeptin (30 mg/kg) in GRMD dogs. Specific Aim #4a: Determine serum bioavailability of oral leupeptin (30mg/kg) in GRMD dogs using mass spectral analysis. Specific Aim #4b: Compare lean body muscle mass and calpain activity between leupeptin and placebo-treated GRMD dogs.

描述（由申请人提供）： 本研究旨在使用犬模型确定钙蛋白酶抑制剂亮抑酶肽在治疗杜氏肌营养不良症（DMD）中的疗效。钙蛋白酶在DMD的发病机制中起重要作用。因此，钙蛋白酶抑制可以为患者提供治疗益处。我们在患有犬肌营养不良症的幼犬中的初步研究表明口服亮抑酶肽具有临床益处。我们打算扩展这些实验使用功能的措施，以评估亮抑酶肽的潜力，作为一种治疗方式的人与DMD。具体目标是： 具体目标#1a：评价口服亮抑酶肽（1-3月龄，每日30 mg/kg）对GRMD犬肌肉功能的疗效，通过最大等长力评估。 具体目标1b：评价口服亮抑酶肽（每日30 mg/kg，1- 3月龄）对GRMD犬临床疾病进展的疗效，如通过跗关节角测量的。 具体目标#2：在DMD犬模型中评价口服亮抑酶肽（1- 3月龄，每天50 mg/kg）对肌肉损伤和坏死的疗效，通过收缩诱导的力缺陷和肌肉活检的组织学评价进行评估 具体目标#3：评价GRMD犬每日经口给予亮抑酶肽（30 mg/kg）的安全性。 具体目的#4a：使用质谱分析测定GRMD犬口服亮抑酶肽（30 mg/kg）的血清生物利用度。具体目标#4b：比较亮抑酶肽和安慰剂治疗的GRMD犬之间的瘦体质量和钙蛋白酶活性。

项目成果

Eccentric contractions induce rapid isometric torque drop in dystrophin-deficient dogs.

偏心收缩会导致肌营养不良蛋白缺陷狗的等长扭矩快速下降。

• DOI: 10.1002/mus.21699
• 发表时间: 2010
• 期刊: Muscle & nerve
• 影响因子: 3.4
• 作者: Tegeler,ChristopherJ;Grange,RobertW;Bogan,DanielJ;Markert,ChadD;Case,Doug;Kornegay,JoeN;Childers,MartinK
• 通讯作者: Childers,MartinK