GENE THERAPY FOR DUCHENNE MUSCULAR DYSTROPHY

杜氏肌营养不良症的基因疗法

• 批准号: 6287091
• 负责人: Jon A Wolff
• 金额: $ 8.3万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6287091
• 关键词: Primates; biotechnology; blood pressure; dogs; dystrophin; gene expression; gene therapy; muscle cells; muscular dystrophy; nonhuman therapy evaluation; plasmids; tight junctions; transfection /expression vector

DESCRIPTION (Copied from Applicant Abstract): Gene therapy promises to be a cure for the muscular dystrophies, such as Duchenne muscular dystrophy. Studies by my laboratory and others indicate that the transfer of the normal human dystrophin gene into dystrophic muscle (in the mouse model) prevents the death of the myofiber. The critical problem now is how to deliver the normal dystrophin gene to enough of the muscle cells and have it stably expressed in order to effect a cure. We have spectacular preliminary results that show that plasmid DNA can be delivered via a blood vessel into more than 10 percent of the muscle cells throughout the leg of a rat. This percentage of transfected muscle cells approaches the critical minimum percentage necessary to be curative in children with Duchenne muscular dystrophy. With this approach, multiple administrations should be possible, ensuring that a sufficient number of cells would be converted to dystrophin-positivity. Our studies also indicate that this approach should lead to stable expression of the gene. We have shown that the intravascular injection of naked plasmid DNA (pDNA) into the femoral artery of rats leads to very high foreign gene expression in skeletal muscle throughout the leg and without damaging the muscle. Previous experience with naked DNA and adenoviral vectors showed that the gene transfer efficiency decreased substantially when going from the young mouse, to adult mouse and then adult rat. The fact that we can achieve very efficient expression in an adult rat is quite encouraging. The objective of this proposal is to extend this approach to larger animals, non-human primates and the dog and its associated Duchenne model. If successful in primates and dogs, a human clinical trial in patients with Duchenne muscular dystrophy could begin in the near future.

描述（从申请人摘要复制）：基因疗法有望成为 治愈肌肉营养不良的肌营养不良，例如Duchenne肌肉营养不良。研究 由我的实验室和其他人指出，正常人的转移 肌营养不良蛋白基因进入营养不良的肌肉（在小鼠模型中）防止死亡 肌纤维。现在关键的问题是如何交付正常 肌营养不良蛋白基因到足够的肌肉细胞，并稳定地表达 为了实现治疗。 我们的初步结果表明质粒DNA可以是 通过血管传递到超过10％的肌肉细胞中 在整个老鼠的腿上。转染的肌肉细胞的百分比 接近儿童治愈所必需的关键最低百分比 伴有肌营养不良的肌营养不良。通过这种方法，多个管理部门 应该有可能，确保足够数量的单元格 转化为肌营养不良蛋白的阳性。我们的研究还表明 方法应导致基因的稳定表达。 我们已经表明，血管内注射裸质粒DNA（pDNA） 大鼠的股动脉导致非常高的外国基因表达 骨骼肌遍布整个腿，而不会损害肌肉。以前的 裸体DNA和腺病毒载体的经验表明基因转移 从年轻小鼠到成人时，效率大大降低 小鼠，然后是成年大鼠。我们可以实现非常有效的事实 成年大鼠的表达是令人鼓舞的。 该提议的目的是将这种方法扩展到大型动物， 非人类灵长类动物和狗及其相关的Duchenne模型。如果成功 在灵长类动物和狗中，人类临床试验对Duchenne肌肉的患者 营养不良可能在不久的将来开始。