Local Intravascular Delivery of Follistatin Gene Therapy for Muscular Dystrophy

描述(申请人提供)：罕见的肌营养不良症涉及多种病因和症状，但几乎所有神经肌肉疾病的特征都是进行性肌肉无力，这是现有治疗方法无法遏制的。肌肉抑制素是许多正在开发的肌营养不良症治疗方法的靶点。肌肉抑制素抑制的临床相关性是基于营养不良条件下肌肉抑制素表达的增加，以及当肌肉抑制素减少时肌肉大小和力量的增加。通过高表达卵泡抑素的载体介导的肌肉生长抑素阻断是一种可行的治疗方法：卵泡抑素是一种有效的肌肉生长抑素拮抗剂，也是病毒载体肌肉内递送的卵泡抑素 结果增加了正常和营养不良组织的肌肉质量和表现。对于某些肌营养不良症，肌肉内注射卵泡抑素可能是一种可行的治疗策略；然而，血管内注射卵泡抑素可能是必要的，以解决与许多神经肌肉疾病相关的全身消耗。包括布莱恩·卡斯帕博士和曾傑瑞·门德尔博士在内的国立儿童医院的研究人员在建立卵泡抑素基因传递的概念证明方面取得了相当大的进展。利用重组腺相关病毒载体治疗方法，他们已经能够建立最有效的启动子系统、载体血清型和优化肢体灌流方法，以安全和良好的耐受性方式实现转基因的强劲表达。这些结果在啮齿动物和非人类灵长类动物身上都得到了证实。在这些发现的基础上，成立了一家名为Milo Biotech的初创公司，将基于卵泡抑素的平台商业化。一项研究局部肌肉注射卵泡抑素-AAV安全性和有效性的I/II期临床试验将于2011年秋季开始。本申请中提出的区域血管内方法将确定rAAV-血清8型卵泡抑素基因治疗的安全性和可行性，并促进后续的IND使能研究。 与公共卫生相关：在美国，肌肉营养不良症影响着大约30万名患者；迫切需要开发治疗方法来对抗肌肉萎缩和提高生活质量。全国儿童医院已经进行了经腺相关病毒(AAV)局部传递卵泡抑素的概念验证的小动物和大动物研究。这项提案寻求在此基础上，进行通过血管系统局部给予的卵泡抑素AAV疗法的初步实验，以治疗系统性肌营养不良。

DESCRIPTION (provided by applicant): Rare muscular dystrophies span a wide range of etiologies and symptoms but nearly all neuromuscular diseases are characterized by progressive muscle weakness that is unchecked by existing therapies. Myostatin inhibition is the target of a number of developing muscular dystrophy therapies. The clinical relevance of myostatin inhibition is based on documented increases in myostatin expression in dystrophic conditions and the increase in muscle size and strength when myostatin is reduced. Vector mediated myostatin blockage by follistatin overexpression is a viable treatment approach: follistatin is a potent myostatin antagonist and viral vector intramuscular delivery of follistatin results in enhanced muscle mass and performance in both normal and dystrophic tissue. Intramuscular gene delivery of follistatin may be a viable treatment strategy for some muscular dystrophies; however, intravascular delivery of follistatin may be necessary to address the systemic wasting associated with many neuromuscular conditions. Researchers at Nationwide Children's Hospital including Dr. Brian Kaspar and Dr. Jerry Mendell have made considerable advances in establishing proof of concept for follistatin gene delivery. Using a recombinant adeno-associated viral vector treatment approach, they have been able to establish the most efficient promoter system, vector serotype and optimize limb perfusion methods to achieve robust transgene expression in a safe and well tolerated manner. These results have been demonstrated in both rodents and non human primates. On the basis of these findings, a start- up company, Milo Biotechnology, was founded to commercialize the follistatin-based platform. A Phase I/II clinical trial to study the safety and efficacy of local intramuscular follistatin-AAV injections will begin in fall 2011. The regional intravascular approach proposed in this application will establish the safety and feasibility of rAAV-serotype8 follistatin gene therapy an facilitate follow-on IND-enabling studies. PUBLIC HEALTH RELEVANCE: Muscular dystrophies affect approximately 300,000 patients in the U.S.; a critical need exists to develop therapies that combat muscle wasting and increase quality of life. Proof-of-concept small and large animal studies in delivering follistatin locally ia adeno-associated virus (AAV) have been done at Nationwide Children's Hospital. This proposal seeks to build on that foundation, conducting initial experiments of a follistatin AAV therapy delivered regionally via the vasculature to treat systemic muscular dystrophies.