Evaluating AAV-mediated gene replacement for Spinal Muscular Atrophy with Respiratory Distress 1

 描述（由申请方提供）：脊髓性肌萎缩伴呼吸窘迫1（SMARD 1）或远端脊髓性肌萎缩（DSMA 1）是一种致死性常染色体隐性遗传疾病，是儿童中第二常见的运动神经元疾病。迄今为止，SMARD 1还没有有效的治疗方法。然而，SMARD 1是基于载体的基因治疗的理想候选者，因为它是单基因的，并且存在合理地概括疾病的重要特征的动物模型。SMARD 1的基因是免疫球蛋白μ结合蛋白2（IGHMBP 2）。IGHMBP 2编码一个993个氨基酸的蛋白质，具有DNA/RNA解旋酶和ATP酶活性，然而，其正常和疾病相关的功能还不清楚。虽然IGHMBP 2广泛表达，但运动神经元是疾病发展中的主要组织，导致包括膈肌在内的骨骼肌明显萎缩。在相关领域如脊髓性肌萎缩症（或近端SMA; 5 q-连锁SMA）中基于载体的基因递送的最新进展已经证明，腺相关病毒（AAV）载体可以有效地进入中枢神经系统和外周内的广泛组织，从而有效地恢复疾病基因的表达。该提案旨在研究基因替代的效用，并提供对疾病发展的见解。

 DESCRIPTION (provided by applicant): Spinal Muscular Atrophy with Respiratory Distress 1 (SMARD1) or Distal Spinal Muscular Atrophy (DSMA1) is a fatal autosomal recessive genetic disorder that is the second most common motor neuron disease in children. To date, no effective therapies or treatments exist for SMARD1. However, SMARD1 is an ideal candidate for vector-based gene therapy since it is monogenic and an animal model exists that reasonably recapitulates important features of disease. The gene responsible for SMARD1 is immunoglobulin µ-binding protein 2 (IGHMBP2). IGHMBP2 encodes a 993 amino acid protein that exhibits DNA/RNA helicase and ATPase activity, however, its normal and disease related functions are not well understood. While IGHMBP2 is ubiquitously expressed, motor neurons are a primary tissue in disease development, resulting in a pronounced wasting of skeletal muscle including the diaphragm. Recent advances in vector-based gene delivery in related areas such as Spinal Muscular Atrophy (or proximal SMA; 5q-linked SMA) have demonstrated that Adeno Associated Virus (AAV) vectors can efficiently enter a broad range of tissues within the central nervous system and the periphery, thereby effectively restoring expression of the disease gene. This proposal is designed to examine the utility of gene replacement as well as provide insight into disease development.