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: 6968002
• 负责人: Martin K Childers
• 金额: $ 17万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 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 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6968002
• 关键词: biopsy; calpain; disease /disorder model; dogs; drug screening /evaluation; enzyme inhibitors; mass spectrometry; muscle disorder chemotherapy; muscle function; muscle pharmacology; muscular dystrophy; nonhuman therapy evaluation; oral administration; pathologic process; pharmacokinetics

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.

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