Gene delivery for fukutin-related protein deficiencies.

针对 fukutin 相关蛋白质缺陷的基因传递。

基本信息

批准号：
9035156
负责人：
Xiao Xiao
金额：
$ 33.57万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9035156
关键词：
Address Adverse effects Affect Animal Model Animals Biochemical Biochemistry Biological Process Capsid Cardiomyopathies Child Clinical Data Dependovirus Disease Dystroglycan Engineering Enzymes Gene Delivery Gene Expression Genes Glycoproteins Goals Health Human Isoleucine Knock-in Lead Leucine Light Limb-Girdle Muscular Dystrophies Liver Longevity MDC1C Measurement Membrane Proteins Methods Missense Mutation Modeling Molecular Molecular Weight Mus Muscle Muscle Proteins Muscle eye brain disease Muscular Dystrophies Mutation Myocardial dysfunction Myocardium Nerve Neuraxis Outcome Pathogenesis Pathology Pathway interactions Patients Peptides Phenotype Physiological Point Mutation Procedures Proline Protein Biochemistry Protein Deficiency Proteins Regulatory Element Route Safety Serotyping Skeletal Muscle Specificity Staging Striated Muscles Testing Therapeutic Tissues Toxic effect Treatment Efficacy Walker-Warburg syndrome adeno-associated viral vector congenital muscular dystrophy curative treatments design early onset effective therapy fukutin related protein gene therapy glycosylation improved in vivo mouse model mutant mutant mouse model natural hypothermia novel overexpression promoter protein expression response success targeted delivery tool transgene expression

项目摘要

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.

描述（由应用提供）：我们的目的是研究与富丁蛋白相关蛋白（FKRP）缺乏的小鼠模型中的基因治疗。 FKRP是一种糖转移酶，是»dystroglycan（�-DG）的糖基化途径中的关键酶之一。 α-DG是肌肉和神经丰富的膜蛋白。 FKRP基因中的突变会引起多种肌肉营养不良。最常见的形式是肢体肌肉营养不良2i（LGMD2I），在后期表现出心肌病。罕见和严重的形式，包括先天性肌肉营养不良症（MDC1C），沃克·瓦尔伯格综合征（WWS）和肌肉 - 眼睛 - 脑疾病（MEB），也表现出中枢神经系统（CNS）缺陷。对于任何肌肉营养不良，在临床上均无法治愈或有效治疗。我们的短期目标是使用新的小鼠模型研究FKRP基因疗法的有效性和安全性，其长期目标是开发有效的与FKRP相关疾病的治疗方法。由于绝大多数FKRP缺陷患者患有LGMD2I，因此我们设计目标1专注于LGMD2I基因疗法，这实际上会发现并受益更多患者。另一方面，严重和早期发作的FKRP相关疾病极为罕见，但会影响患有中枢神经系统并发症的幼儿。因此，我们的目标是专门针对这种类型的疾病，重点是CNS基因递送。 FKRP缺乏症的研究不足，其基本生物化学并没有像大多数定义明确的经典酶那样彻底理解。结果，我们提出了目标3，以进一步阐明FKRP的体内功能，以获取基因治疗的有用信息和指导。