Gene delivery for fukutin-related protein deficiencies.

描述（由申请人提供）：我们的目的是研究Fukutin相关蛋白（FKRP）缺乏症小鼠模型的基因治疗。FKRP是一种糖基转移酶，是<$-肌营养不良聚糖（<$-DG）糖基化途径中的关键酶之一。α-DG是一种在肌肉和神经中含量丰富的膜蛋白。FKRP基因突变可导致一系列肌营养不良症。最常见的形式是肢带型肌营养不良症2 I（LGMD 2 I），在后期表现为心肌病。罕见和严重的形式，包括先天性肌营养不良症（MDC1C），沃克-沃伯格综合征（WWS）和肌肉-眼-脑疾病（MEB），也显示中枢神经系统（CNS）缺陷。临床上没有治愈性或有效的治疗方法可用于任何肌营养不良症。我们的短期目标是利用新的小鼠模型研究FKRP基因治疗的有效性和安全性，长期目标是开发FKRP相关疾病的有效治疗方法。由于绝大多数FKRP缺陷患者患有LGMD2I，因此我们设计目标1以关注LGMD2I基因治疗，这将实际发现并受益于更多患者。另一方面，重度和早发性FKRP相关疾病极为罕见，但它们影响患有CNS并发症的幼儿。因此，我们的目标2致力于这种类型的疾病，重点是中枢神经系统基因传递。FKRP缺乏症一直研究不足，其基本生物化学不像大多数定义明确的经典酶那样彻底理解。因此，我们提出了目的3，进一步阐明FKRP的体内功能，为基因治疗提供有用的信息和指导。

DESCRIPTION (provided by applicant): Our purpose is to study gene therapy in mouse models of Fukutin-related protein (FKRP) deficiency. FKRP is a glycotransferase, one of the key enzymes in the glycosylation pathway of ¿-dystroglycan (¿-DG). Alpha-DG is a membrane protein abundant in muscle and nerve. Mutations in FKRP gene cause a spectrum of muscular dystrophies. The most common form is limb girdle muscular dystrophy 2I (LGMD2I) that manifests cardiomyopathy at later stage. The rare and severe forms, including congenital muscular dystrophy (MDC1C), Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB), also show central nervous system (CNS) deficiency. No curative or effective treatment is clinically available for any muscular dystrophies. Our short-term goal is to use the new mouse models to study FKRP gene therapy efficacy and safety, with the long-term goal to develop an effective treatment for FKRP-related diseases. Since the vast majority of the FKRP-deficient patients suffer from LGMD2I, we design Aim 1 to focus on LGMD2I gene therapy, which will practically find and benefit many more patients. On the other hand, the severe and early-onset FKRP- related diseases are extremely rare but they affect young children with CNS complications. We therefore have Aim 2 dedicated to this type of diseases with an emphasis on CNS gene delivery. FKRP deficiency has been under-studied and its basic biochemistry is not as thoroughly understood as most of the well-defined classic enzymes. As a result, we put forth Aim 3 to further elucidate the in vivo functions of FKRP, to gain useful information and guidance for gene therapy.