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：
8714274
负责人：
Gabriela Denning
金额：
$ 65.91万
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 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8714274
关键词：
A Mouse Antithymoglobulin Autologous Transplantation Biomedical Engineering Biotechnology Blood Coagulation Factor Blood coagulation Businesses Busulfan CD34 gene CSF3 gene Caring Cells Child Clinical Clinical Research Clinical Trials Clinical Trials Design Complementary DNA Coupled Data Development Disease Effectiveness Elements Engraftment Factor VIII Family suidae Gene Dosage Gene Transfer Genetic Engineering Goals Guidelines Healthcare Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Hemophilia A Hemorrhage Human Human Resources Hybrids IL2 gene Individual Institutional Review Boards Intravenous infusion procedures Investigational Drugs Investigational New Drug Application Knockout Mice Life Mesenchymal Stem Cells Modeling Mus Mutagenicity Tests New Drug Approvals Patients Persons Phase Physicians Plasma Pre-Clinical Model Principal Investigator Production Property Recombinants Recruitment Activity Regimen Research Personnel Running Safety Series Small Business Innovation Research Grant Staging Stem cell transplant Subfamily lentivirinae Technology Therapeutic Transgenes Translations Transplantation Universities Xenograft Model base cellular transduction clinical application conditioning design follow-up gene therapy gene therapy clinical trial genetically modified cells human F8 protein improved inhibitor/antagonist man meetings pre-clinical preclinical study programs public health relevance recombinant antihemophilic factor VIII response safety testing vector

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this proposal is to conduct a gene therapy clinical trial incorporating genetically modified hematopoietic stem cells (HSCs) for persons with hemophilia A. In a series of recent studies, we have shown that the transplantation of genetically-engineered HSCs can restore factor VIII (fVIII) activity to curative levels in hemophilia A mice and that human HSCs are readily transduced with recombinant lentivector encoding a genetically-engineered fVIII transgene. Our gene therapy approach uses a bioengineered fVIII transgene designed at Emory University and contains critical high-expression sequences, which we have shown are necessary and sufficient to achieve therapeutic/curative fVIII expression levels. Using the bioengineered fVIII construct, designated ET-3, in preclinical murine studies we routinely observe normal fVIII activity levels (1 unit/ml) i mice engrafted with 1 - 5% genetically-modified hematopoietic cells. These engraftment levels are similar to those that have already been achieved in human HSC-based clinical gene therapy trials. In contrast, we and others have shown that similar strategies using fully human fVIII sequences do not achieve these robust fVIII activity levels in the hemophilia A mouse preclinical model. We have generated extensive preclinical data using the ET-3 transgene, which demonstrate proof-of-concept that HSCs genetically engineered with ET-3-encoding lentivector, coupled with a non-myeloablative transplant regimen, can be used to treat and possibly cure hemophilia A. In addition, a favorable pre-IND meeting was held that provided the necessary guidance needed to finalize our preclinical data package and vector manufacturing. We now propose to 1) generate late-stage preclinical data using clinical-grade (GMP) lentivector product, 2) complete the regulatory submissions necessary for approval to conduct a pilot gene therapy clinical trial and 3) recruit and treat 7 patients with hemophilia A in the proposed trial. Four organizations have partnered to accomplish these aims, including: i) Expression Therapeutics, LLC, a biotechnology company founded on the high expression fVIII technology, ii) Emory University, where the majority of the preclinical studies have been performed, iii) Children's Healthcare of Atlanta, a financial supporter of the Gene Therapy Program at Emory University and investor in Expression Therapeutics, and iv) Lentigen Corporation, a company dedicated to the successful clinical application of lentivectors. Lentigen will generate the clinical lentivecto product that will be used in the proposed studies including the clinical trial, and the trial will e conducted at Emory University by expert principal investigators with clinical expertise in stem cell transplantation and the treatment of hemophilia A. The chief milestone of the current Phase II SBIR proposal is the translation of the ET-3 gene therapy concept and project from the late-pre-clinical study phase into a first-in-man trial.

描述（由申请人提供）：该提案的总体目标是针对血友病的人进行一项基因治疗临床试验，该试验纳入了遗传改良的造血干细胞（HSC）。很容易用编码遗传学的FVIII转基因的重组烯烃转导的转导。我们的基因疗法方法使用埃默里大学设计的生物工程FVIII转基因，并包含关键的高表达序列，我们已经证明这是必要的，足以实现治疗/治疗性FVIII表达水平。在临床前鼠研究中，使用指定的ET-3的生物工程FVIII构建体，我们通常观察到正常的FVIII活性水平（1单位/ml）I小鼠，该I小鼠植入了1-5％遗传性的造血细胞。这些植入水平与在基于人类HSC的临床基因治疗试验中已经达到的植入水平相似。相反，我们和其他人表明，使用人类FVIII序列的类似策略不能达到小鼠临床前模型中的这些强大的FVIII活性水平。我们已经使用ET-3转基因生成了广泛的临床前数据，这证明了概念证明，HSC在遗传上使用ET-3编码的盐探测器进行了遗传设计，并与非层状移植方案相结合，可以用于治疗良好的预处理，以确保良好的预定范围，可以使用良好的预处理。现在，我们提议1）使用临床级（GMP）lentivector产品生成晚期临床前数据，2）完成批准进行试验基因治疗临床试验所需的调节性提交和3）在拟议的试验中招募和治疗7例血友病A患者。 Four organizations have partnered to accomplish these aims, including: i) Expression Therapeutics, LLC, a biotechnology company founded on the high expression fVIII technology, ii) Emory University, where the majority of the preclinical studies have been performed, iii) Children's Healthcare of Atlanta, a financial supporter of the Gene Therapy Program at Emory University and investor in Expression Therapeutics, and iv) Lentigen Corporation,一家致力于成功植物临床应用的公司。扁豆将生成临床遗嘱分型产品，该产品将用于包括临床试验在内的拟议研究中，并且该试验将由具有干细胞移植和血友病的临床专业知识的专家专业研究者在埃默里大学进行E试验。