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

基本信息

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
项目类别：
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

项目摘要

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）：本提案的总体目标是进行后期临床前研究，以支持针对甲型血友病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，我们表明基因工程造血干细胞移植可以将血友病 A 小鼠中的因子 VIII (fVIII) 活性恢复至治疗水平，并且人类造血干细胞很容易用重组转导编码基因工程 fVIII 转基因的慢病毒。迄今为止，我们是唯一一个使用常规临床实践中的非清髓性移植方案在 A 型血友病小鼠中获得持续治疗性 fVIII 表达水平的团队。我们的基因治疗方法使用生物工程化的 fVIII 转基因（称为 ET-3），可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)，目前在人类基因治疗临床试验中已达到这一水平。我们使用 ET-3 生成了广泛的临床前数据，证明了用编码 ET-3 的慢病毒载体进行基因工程改造的造血干细胞，结合非清髓性移植方案，可用于治疗 A 型血友病。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。预计后续二期项目将提交以支持实际的临床试验。四个组织合作实现这些目标，包括：i) Expression Therapeutics, LLC，一家基于高表达 fVIII 技术成立的生物技术公司，ii) 埃默里大学，高表达 fVIII 技术的构思和概念验证发生地，iii)亚特兰大儿童保健中心、埃默里大学基因治疗项目的财务支持者和 Expression Therapeutics, LLC 的投资者，以及 iv) Lentigen Corporation，一家致力于慢病毒载体成功临床应用的公司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载体将用于拟议的研究，包括临床试验。公众健康相关性：凝血因子 VIII 表达不足会导致出血性疾病 A 型血友病。目前对该疾病的治疗包括困难、长期静脉输注血浆衍生或重组因子 VIII，以恢复循环因子 VIII 活性水平由于产品成本高且供应有限，目前仅向不到三分之一的 A 型血友病患者提供该产品。基因疗法为这种使人衰弱且在世界许多地区致命的疾病提供了潜在的治疗方法。我们已经证明，移植经过基因改造以表达工程因子 VIII 蛋白的骨髓细胞是治疗 A 型血友病的可行方法。在当前的申请中，我们建议进行后期临床前测试，以支持首个临床试验的批准。男性临床基因治疗审判。