Local Intravascular Delivery of Follistatin Gene Therapy for Muscular Dystrophy

描述（由申请人提供）：罕见的肌肉营养不良症有广泛的病因和症状，但几乎所有的神经肌肉疾病都以进行性肌肉无力为特征，而现有的治疗方法无法抑制这种症状。肌生长抑制素抑制是许多发展中的肌萎缩症治疗的目标。肌生长抑制素抑制的临床意义是基于在营养不良条件下肌生长抑制素表达的增加，以及当肌生长抑制素减少时肌肉大小和力量的增加。载体介导的卵泡抑素过表达导致的肌肉生长抑制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制素拮抗剂，也是一种肌内递送卵泡抑素的病毒载体

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.