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（由申请人提供）：该提案的总体目标是进行晚期临床前研究，以支持造血干细胞移植基因治疗对血友病的试验临床试验。人类造血干细胞很容易被编码遗传学的FVIII转基因的重组慢病毒转导。迄今为止，我们是唯一使用常规临床实践中的非骨髓性移植方案获得了血友病A小鼠中持续治疗性FVIII表达水平的群体。我们的基因治疗方法使用生物工程的FVIII转基因（称为ET-3），该转基因在造血干细胞转导效率（1-5％）下达到正常的FVIII活性水平（1单位/mL），目前在人类基因疗法临床试验中已实现。我们已经使用ET-3生成了广泛的临床前数据，证明了概念概念表明，造血干细胞用慢烟病毒载体进行了遗传学的ET-3，再加上非层状移植方案，可以使用非层状移植方案来治疗血友病。因此，我们的后期测试将基于FDA指导。其次，我们将使用临床级（GMP）慢病毒载体编码ET-3生成最终的临床前数据集，该齿病毒矢量将专门检验临床产品的安全性和有效性。抗衰原的是，将提交一个随访第二阶段项目以支持实际的临床试验。 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是一家致力于慢病毒媒介的临床应用，也是最大的慢病毒媒介知识产权投资组合的持有人。扁豆将产生 临床级重组烯烃将在拟议的研究中使用，包括临床试验。 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.基因疗法可提供这种令人衰弱的治疗方法，在世界许多地方，致死性疾病。我们已经表明，对遗传修饰以表达工程因子VIII蛋白的骨髓细胞的移植是对血友病A的可行治疗。 审判。