Sleeping Beauty-Mediated Gene Therapy for Hemophilia

睡美人介导的血友病基因治疗

• 批准号: 6883402
• 负责人: PERRY B. HACKETT
• 金额: $ 59.54万
• 依托单位: DISCOVERY GENOMICS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6883402
• 关键词: Sleeping; Beauty; Mediated; Gene; Therapy

DESCRIPTION (provided by applicant): Hemophilia A is a bleeding disorder caused by the absence of clotting factor VIII (FVIII). This disease is inherited in an X-linked recessive manner. There are 15,000 affected individuals in the U.S. Treatment of Hemophilia A is based on frequent delivery of recombinant FVIII (recombinate). However, the high expense of this treatment (as much as $100,000 per year in severe cases) and variable levels of FVIII maintained in the circulation compromise the effectiveness of this therapy. FVIII gene therapy represents a more efficacious and cost-effective treatment of the disease. We propose continued development of the Sleeping Beauty (SB) transposon system in a Phase II study of non-viral FVIII-gene transfer and expression in the liver as a therapeutic approach for hemophilia A. This approach is based on results from our Phase I studies of long-term, SB transposon-mediated FVIII gene expression in livers of FVIII-deficient mice. We hypothesize that the FVIII gene can similarly be delivered and expressed in the livers of larger animals (ultimately, humans), providing long-term and curative expression of FVIII. These goals are addressed in four Specific Aims. In Aim 1 we will test for SB-mediated long-term expression of reporter genes and the FVIII gene in the livers of mice after delivery of transposon and transposase components directly to the hepatic circulation via retroductal delivery. In Aim 2 we will determine the efficacy of using DNA, DNA-polycation complexes or other DNA complexes for delivery of transposons to liver. These conditions will then be used in Aim 3 to test for SB-mediated long-term expression of reporter genes in the livers of dogs as a large animal model for in vivo gene transfer. In Aim 4, results from the experiments in normal dogs will be used to evaluate the SB system for transposition and long-term expression of the canine FVIII gene in a dog model of hemophilia A, testing for improved clotting and correction of the bleeding disorder. At every stage we will examine animal tissues for histopathological indications of adverse events. Results from these preclinical studies will position DGI for submission of an Investigational New Drug application (IND) to the FDA, with subsequent initiation of a clinical trial testing the effectiveness of the SB system FVIII gene therapy in human subjects. Technological Innovation: Sleeping Beauty is a novel gene transfer system with potential application in gene therapy. The market size for the inherited-diseases market niche, to which this technology applies is about $5.8 billion.

描述（由申请方提供）：血友病A是一种由凝血因子VIII（FVIII）缺乏引起的出血性疾病。这种疾病是以X连锁隐性方式遗传的。在美国有15，000名受影响的个体。血友病A的治疗基于重组FVIII（重组）的频繁递送。然而，这种治疗的高费用（在严重病例中每年高达100，000美元）和在循环中维持的可变水平的FVIII损害了这种疗法的有效性。FVIII基因治疗是一种更有效和更具成本效益的疾病治疗。我们建议在肝脏中非病毒FVIII基因转移和表达的II期研究中继续开发睡美人（SB）转座子系统，作为血友病A的治疗方法。这种方法是基于我们的长期，SB转座子介导的FVIII基因在FVIII缺陷小鼠的肝脏表达的I期研究的结果。我们假设FVIII基因可以类似地在较大动物（最终是人类）的肝脏中递送和表达，从而提供FVIII的长期和治愈性表达。这些目标在四个具体目标中得到实现。在目的1中，我们将测试SB介导的报告基因和FVIII基因在小鼠肝脏中的长期表达，之后通过导管后递送将转座子和转座酶组分直接递送至肝循环。在目的2中，我们将确定使用DNA、DNA-聚阳离子复合物或其他DNA复合物将转座子递送至肝脏的功效。然后将这些条件用于目标3，以检测SB介导的报告基因在犬肝脏中的长期表达，作为体内基因转移的大型动物模型。在目的4中，将使用正常犬的实验结果评价SB系统在血友病A犬模型中犬FVIII基因的转座和长期表达，检测凝血改善和出血性疾病的纠正。在每个阶段，我们将检查动物组织中不良事件的组织病理学指标。这些临床前研究的结果将使DGI能够向FDA提交研究性新药申请（IND），随后启动临床试验，测试SB系统FVIII基因治疗在人类受试者中的有效性。技术创新：睡美人是一种新型的基因转移系统，在基因治疗中具有潜在的应用前景。这项技术所适用的遗传性疾病市场利基的市场规模约为58亿美元。