Development of highly efficient factor VIII mini-gene therapy

开发高效因子VIII小基因疗法

基本信息

批准号：
9198944
负责人：
WEIDONG XIAO
金额：
$ 48.73万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198944
关键词：
Adverse effects Affect Amino Acid Substitution Amino Acids Animal Model Blood Coagulation Disorders Blood Coagulation Factor Canis familiaris Clinical Trials Code Codon Nucleotides Complementary DNA Cues DNA cassette Development Disease Dose Engineering Epitopes F8 gene Factor IX Factor V Factor VIII Family suidae Gene Delivery Gene Targeting Genes Goals Hemophilia A Hemophilia B Hereditary Disease Human Human Activities Human Engineering Intravenous infusion procedures Lead Medicine Methods Modeling Mus Mutate Names Other Genetics Patients Population Positioning Attribute Property Proteins Quality of life Rattus Recombinant adeno-associated virus (rAAV)Recombinants Regulatory Element Technology Variant Work X Chromosome adeno-associated viral vector cost design enzyme replacement therapy experimental study gene therapy improved inhibitor/antagonist male nonhuman primate novel preclinical study prevent promoter public health relevance screening success vector

项目摘要

DESCRIPTION (provided by applicant): Approximately one in 5000 males in human population suffers from coagulation disorder, hemophilia A. This disease is primarily caused by deficiency in the factor VIII gene located in the X-chromosome and is difficult to treat by conventional medicine. Current treatment of hemophilia A by intravenous infusion of factor VIII concentrates is very costly and has a potential side effect of developing inhibitors. Gene therapy, on the other hand, can potentially prevent these limitations of current treatments. Although recombinant adeno-associated virus (rAAV) vectors are promising for deliver factor VIII gene, applying AAV vector technology to Hemophilia A gene therapy lagged behind other genetic diseases because of this size constraint (limited to ~5kb) and inefficient secretion of factor VIII protein. To improve factor VIII gene delivery utilizing rAAV vectors, we will develop a novel human factor VIII molecules with enhanced expression and secretion. The specific aims for this proposal are: 1). To develop a human factor VIII molecule with improved secretion and expression; 2). To develop a human factor VIII molecule with enhanced specific activity with minimal amino acid alteration; 3). To optimize the AAV factor VIII packaging and expression cassette and carry out preclinical studies in Hemophilia Animal Model. The success of this proposal may lead to a clinical trial of hemophilia A using AAV vectors.

描述（申请人提供）：人类中大约每 5000 名男性中就有 1 人患有凝血障碍，即血友病 A。这种疾病主要是由位于 X 染色体的因子 VIII 基因缺陷引起的，用常规药物很难治疗。目前通过静脉注射凝血因子 VIII 浓缩物治疗 A 型血友病的方法非常昂贵，并且存在开发抑制剂的潜在副作用，而基因疗法则有可能预防这种疾病。目前治疗的这些局限性虽然重组腺相关病毒 (rAAV) 载体有望用于传递因子 VIII 基因，但由于大小限制（限制为约 5kb）和将 AAV 载体技术应用于血友病 A 基因治疗，落后于其他遗传疾病。因子 VIII 蛋白的低效分泌为了利用 rAAV 载体改善因子 VIII 基因的递送，我们将开发一种具有增强的表达和分泌的新型人因子VIII分子。 2)开发具有增强的特异性活性的人因子VIII分子。最小的氨基酸改变；3).优化AAV因子VIII的包装和表达盒并在血友病动物模型中进行临床前研究。该提案的成功可能会导致血友病A的临床试验。使用 AAV 载体。