In Vivo Editing for Hemophilia Gene Therapy

血友病基因治疗的体内编辑

• 批准号: 9695292
• 负责人: David Terry Curiel
• 金额: $ 21.51万
• 依托单位: PRECISION VIROLOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9695292
• 关键词: Vivo; Editing; Hemophilia; Gene; Therapy

Project Summary The exceptional promise of gene therapy for hemophilia has been shown in recent studies that result in long term correction of factor IX deficiency, via hepatic transduction with an adeno-associated vector (AAV). In spite of this watershed event in the history of the gene therapy field, there presently exist barriers to the fullest implementation of hemophilia gene therapy. The limited packaging capacity of AAV for larger gene constructs practically confounds the use of this vector for factor VIII correction and vector-related toxicities have been noteworthy for the context of in vivo transduction of the liver. We propose to develop a novel vector approach that addresses these limitations. Of note, our recent strategies to retarget adenoviral vectors (Ad) have allowed mitigation of vector-associated liver toxicities and in vivo transduction of the pulmonary endothelium that has demonstrated that this site can serve as a fully effective platform to reconstitute deficient serum proteins. Moreover, new generation Ads with multiple deletions can be modified to incorporate an expanded range of gene constructs and larger payloads relevant to gene therapy for the full spectrum of hemophilia disorders. We propose to utilize the CRISPR/Cas 9 system which is fully commensurate with Ad technology, in conjunction with our pulmonary endothelial-targeted Ad, to achieve stable incorporation of corrective hemophilia genes within the pulmonary endothelium. Our novel strategy thereby offers the potential for stable genetic correction in a manner that circumvents potential vector-associated toxicities for both factor IX and factor VIII hemophilia. Successful completion of the aims within this proof of feasibility Phase 1 STTR will set the stage for the application of corrective gene therapy for hemophilia to the widest context of patients and provide the rationale for translational development of our highly novel approach into lead optimization and selection in Phase II. Our groups have unparalleled track records for successful bench-to-bed translation of novel gene therapy strategies. Our strategy to accomplish stable expression of deficient hemophilia factors deriving from a pulmonary vascular source clearly represents a highly original approach. In addition to circumventing the issue of vector-mediated hepatotoxicities, the expanded packaging capacity of adenovirus vectors also feasibilizes gene therapy for factor VIII, as well as factor IX deficiency disorders. To hasten translation of our approach, we will utilize adenoviral vectors derived from non-human primate adenoviruses and will specifically use gorilla Ad vectors (GAd) that address a pivotal human use barrier by circumventing preformed adenoviral immunity and are show excellent performance characteristics in therapeutic applications. The profile of efficacy studies herein will constitute the rationale for translational development of this novel approach as well as a leap to establishing the pulmonary endothelium as a source to provide secreted factors as an important strategy for the range of inherited genetic disorders based upon deficient serum factors as well as other potential therapeutic applications.

项目概要 最近的研究显示了基因治疗血友病的非凡前景，这些研究导致 通过腺相关载体 (AAV) 的肝转导，长期纠正因子 IX 缺乏症。在 尽管这是基因治疗领域历史上的分水岭事件，但目前仍存在充分的障碍 实施血友病基因治疗。 AAV 对于较大基因构建体的包装能力有限 实际上混淆了该载体用于因子 VIII 校正的用途，并且与载体相关的毒性已被 值得注意的是肝脏体内转导的背景。我们建议开发一种新颖的矢量方法 解决了这些限制。值得注意的是，我们最近重新定位腺病毒载体（Ad）的策略已经允许 减轻载体相关的肝脏毒性和肺内皮的体内转导 证明该位点可以作为重建缺陷血清蛋白的完全有效的平台。 此外，可以修改具有多个删除的新一代广告，以纳入更广泛的内容 与全谱血友病基因治疗相关的基因构建体和更大的有效负载。我们 提出利用与Ad技术完全相当的CRISPR/Cas 9系统，结合 与我们的肺内皮靶向 Ad 一起，实现纠正血友病基因的稳定掺入 肺内皮内。因此，我们的新策略提供了稳定遗传校正的潜力 以规避因子 IX 和因子 VIII 血友病潜在载体相关毒性的方式。 成功完成本可行性证明阶段 1 STTR 中的目标将为 将血友病纠正基因疗法应用于最广泛的患者并提供理论依据 用于将我们高度新颖的方法转化为第二阶段先导化合物优化和选择。我们的 小组在新型基因疗法的成功从实验室到临床转化方面拥有无与伦比的记录 策略。我们的策略是实现源自血友病因子的缺陷的稳定表达 肺血管来源显然代表了一种高度原创的方法。除了规避问题之外 载体介导的肝毒性，腺病毒载体的扩展包装能力也使 因子 VIII 以及因子 IX 缺乏症的基因治疗。为了加快我们方法的转化，我们 将利用源自非人类灵长类腺病毒的腺病毒载体，并将专门使用大猩猩Ad 通过规避预先形成的腺病毒免疫来解决关键的人类使用障碍的载体（GAd） 在治疗应用中表现出优异的性能特征。功效研究概况 这里将构成这种新颖方法的转化发展的基本原理以及向 建立肺内皮作为提供分泌因子的来源作为重要策略 基于血清因子缺陷以及其他潜在因素的一系列遗传性疾病 治疗应用。