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: 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
• 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

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(申请人提供)：这项建议的总体目标是为血友病A患者进行一项整合转基因造血干细胞的基因治疗临床试验。在最近的一系列研究中，我们发现移植基因工程的造血干细胞可以将血友病A小鼠的因子VIII(FVIII)活性恢复到治疗水平，并且人的造血干细胞很容易通过编码基因工程的FVIII转基因的重组慢载体转导。我们的基因治疗方法使用了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，这些序列对于达到治疗/治愈FVIII的表达水平是必要的和足够的。使用命名为ET-3的生物工程FVIII结构，在临床前小鼠研究中，我们常规观察植入1-5%转基因造血细胞的正常FVIII活性水平(1个单位/毫升)I小鼠。这些植入水平与人类基于HSC的临床基因治疗试验中已经达到的水平相似。相反，我们和其他人已经证明，在血友病A小鼠临床前模型中，使用完全人类FVIII序列的类似策略并不能达到这些强大的FVIII活性水平。我们已经使用ET-3转基因产生了大量的临床前数据，这证明了概念验证，即以ET-3编码的慢病毒载体进行基因工程的HSCs，结合非清髓性移植方案，可以用于治疗并可能治愈血友病A。此外，还举行了有利的IND前会议，提供了敲定我们的临床前数据包和载体制造所需的必要指导。我们现在建议1)使用临床级(GMP)慢病毒载体产品生成晚期临床前数据，2)完成必要的监管提交，以批准进行试点基因治疗临床试验，以及3)在拟议的试验中招募和治疗7名血友病A患者。为了实现这些目标，四个组织结成了合作伙伴，其中包括：i)Expression Treateutics，LLC，一家建立在高表达FVIII技术之上的生物技术公司；ii)埃默里大学，大多数临床前研究都在那里进行；iii)亚特兰大儿童医疗保健公司，Emory大学基因治疗计划的资金支持者和Expression Treeutics的投资者；以及iv)Lentigen公司，一家致力于慢病毒载体的成功临床应用的公司。Lentigen将生产将用于包括临床试验在内的拟议研究的临床微透镜产品，该试验将由在干细胞移植和血友病A治疗方面具有临床专业知识的专家首席研究员在埃默里大学进行。当前第二阶段SBIR提案的主要里程碑是将ET-3基因治疗概念和项目从晚期临床前研究阶段转化为首个人试验。