Bioengineered factor VIII gene therapy for hemophilia A

针对血友病 A 的生物工程因子 VIII 基因治疗

• 批准号: 8313425
• 负责人: Gabriela Denning
• 金额: $ 37.85万
• 依托单位: EXPRESSION THERAPEUTICS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2013-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313425
• 关键词: A Mouse; Autologous; Biochemical; Biomedical Engineering; Biotechnology; Blood Clot; Blood Coagulation Factor; Blood coagulation; Bone Marrow Cell Transplantation; Businesses; CD34 gene; Cells; Child; Clinical; Clinical Trials; Clinical Trials Design; Clinical effectiveness; Conceptions; Coupled; Data; Data Set; Development; Disease; Effectiveness; Engineering; Factor VIII; Funding; Genetic; Goals; Healthcare; Hematopoietic stem cells; Hemophilia A; Hemorrhage; Human; Human Resources; Individual; Intellectual Property; Intravenous infusion procedures; Investigation; Lead; Legal patent; Lentivirus Vector; Marketing; Modification; Mus; Participant; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Physicians; Plasma; Preclinical Testing; Property; Proteins; Recombinants; Regimen; Research Personnel; Safety; Series; Small Business Innovation Research Grant; Staging; Subfamily lentivirinae; System; Technology; Testing; Therapeutic; Transgenes; Transplantation; United States Food and Drug Administration; Universities; Virus; Xenograft Model; base; cellular transduction; clinical application; clinical practice; conditioning; cost; design; expectation; follow-up; gene therapy; gene therapy clinical trial; genetically modified cells; genotoxicity; immunogenic; man; meetings; pre-clinical; pre-clinical research; preclinical study; programs; quality assurance; recombinant antihemophilic factor VIII; research and development; research clinical testing; safety testing; transduction efficiency; transgene expression

DESCRIPTION (provided by applicant): The overall goal of this proposal is to conduct late-stage preclinical studies to support a pilot clinical trial of hematopoietic stem cell transplantaton gene therapy for hemophilia A. In a series of recent studies, we have shown that the transplantation of genetically-engineered hematopoietic stem cells can restore factor VIII (fVIII) activity to curative levels in hemophilia A mice and that human hematopoietic stem cells are readily transduced with recombinant lentivirus encoding a genetically-engineered fVIII transgene. To date, we are the only group that has obtained sustained therapeutic fVIII expression levels in hemophilia A mice using non- myeloablative transplantation regimens that are in routine clinical practice. Our gene therapy approach uses a bioengineered fVIII transgene (termed ET-3) that achieves normal fVIII activity levels (1 unit/ml) at hematopoietic stem cell transduction efficiencies (1-5%), which are achieved currently in human gene therapy clinical trials. We have generated extensive preclinical data using ET-3 demonstrating proof-of-concept that hematopoietic stem cells genetically engineered with a lentivirus vector encoding ET-3, coupled with a non-myeloablative transplant regimen, can be used to treat hemophilia A. We now propose to first conduct pre-IND meetings with the FDA to direct final preclinical testing of ET-3. Therefore, our late stage testing will be based on FDA guidance. Second, we will generate our final preclinical data set using clinical- grade (GMP) lentiviral vector encoding ET-3, which will specifically test the safety and effectiveness of the clinical product. It is anticipted that a follow up phase II project will be submitted in support of the actual clinical trial. Four organizations have partnered to accomplish these goals, including: i) Expression Therapeutics, LLC, a biotechnology company founded on the high expression fVIII technology, ii) Emory University, where the conception and proof of concept of high expression fVIII technology occurred, iii) Children's Healthcare of Atlanta, financial supporter of the Gene Therapy Program at Emory University and investor in Expression Therapeutics, LLC, and iv) Lentigen Corporation, a company dedicated to the successful clinical application of lentiviral vectors and holder of the largest lentiviral vector intellectual property portfolio. Lentigen will generate the clinical-grade recombinant lentivector that will be used in the proposed studies including the clinical trial. PUBLIC HEALTH RELEVANCE: Insufficient expression of the blood clotting factor VIII results in the bleeding disorder hemophilia A. Current treatment for this disease consists of difficult, lie-long, intravenous infusion of plasma-derived or recombinant factor VIII to restore circulating factor VIII activity levels and is currently offered to less than one-third of all hemophilia A patients due to high product cost and limited availability. Gene therapy offers a potential cure fo this debilitating and, in many parts of the world, lethal disease. We have shown that transplantation of bone marrow cells genetically-modified to express an engineered factor VIII protein is a feasible treatment for hemophilia A. In the current application, we propose to conduct late-stage pre-clinical testing to support approval of a first in man clinical gene therapy trial.

描述(申请人提供)：这项建议的总体目标是进行后期临床前研究，以支持血友病A的造血干细胞移植基因治疗的试点临床试验。在最近的一系列研究中，我们已经证明，移植基因改造的造血干细胞可以将血友病A小鼠的凝血因子VIII(FVIII)活性恢复到治疗水平，并且人类造血干细胞很容易被编码基因改造的FVIII转基因的重组慢病毒转导。到目前为止，我们是唯一一组在常规临床实践中使用非清髓性移植方案在血友病A小鼠中获得持续治疗性FVIII表达水平的小组。我们的基因治疗方法使用生物工程FVIII转基因基因(称为ET-3)，在造血干细胞转导效率(1-5%)下获得正常的FVIII活性水平(1单位/毫升)，这是目前在人类基因治疗临床试验中实现的。我们已经使用ET-3生成了大量的临床前数据，证明了通过编码ET-3的慢病毒载体进行基因工程的造血干细胞，结合非清髓性移植方案，可以用于治疗血友病A。我们现在建议首先与FDA举行IND前会议，以指导ET-3的最终临床前测试。因此，我们的后期测试将基于FDA的指导。其次，我们将使用编码ET-3的临床级(GMP)慢病毒载体生成最终的临床前数据集，这将专门测试临床产品的安全性和有效性。预计将提交后续第二阶段项目，以支持实际的临床试验。为了实现这些目标，四个组织已经结成了合作伙伴：i)Expression Treateutics，LLC，一家建立在高表达FVIII技术基础上的生物技术公司；ii)Emory大学，高表达FVIII技术的概念并进行概念验证的地方；iii)亚特兰大的儿童医疗保健公司，Emory大学基因治疗计划的资金支持者和Expression Treateutics公司的投资者；iv)Lentigen公司，一家致力于慢病毒载体的成功临床应用的公司，并且拥有最大的慢病毒载体知识产权组合。Lentigen将生成 临床级重组慢病毒载体，将用于拟议的研究，包括临床试验。 公共卫生相关性：凝血因子VIII的表达不足导致出血性疾病血友病A。目前对这种疾病的治疗包括长时间静脉输注血浆衍生的或重组因子VIII以恢复循环因子VIII的活性水平，由于产品成本高和可获得性有限，目前只提供给不到三分之一的血友病A患者。基因疗法为这种令人衰弱的疾病提供了一种潜在的治疗方法，在世界许多地区，这种疾病都是致命的。我们已经证明，移植基因修饰的表达基因viii蛋白的骨髓细胞是治疗血友病A的一种可行的治疗方法。在目前的应用中，我们建议进行后期的临床前测试，以支持批准人类第一个临床基因治疗。 审判。