FIV Vectors for the Treatment of Hemophilia A

用于治疗 A 型血友病的 FIV 载体

• 批准号: 6992338
• 负责人: Sybille L Sauter
• 金额: $ 10万
• 依托单位: VIROGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-22 至 2007-01-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6992338
• 关键词: animal genetic material tag; biotechnology; coagulation factor VIII; feline immunodeficiency virus; gene delivery system; gene therapy; green fluorescent proteins; hemophilia As; human genetic material tag; immune response; laboratory mouse; plasmids; polymerase chain reaction; technology /technique development; transfection /expression vector

DESCRIPTION (provided by applicant): The current standard of care for hemophilia A is treatment with intravenous FVIII protein infusions, either prophylacticly or during bleeding episodes. Prophylactic treatment, however, is problematic due to limited availability, high costs and concerns for blood-borne diseases due to venous access. Gene transfer with viral vectors provides an attractive alternative therapeutic approach with the potential for long-term correction since only 5% of normal FVIII expression levels provide substantial clinical benefits. Success of clinical trials with adeno (Ad)- and oncoretroviral (MLV) FVIII therapy has been compromised to date by lack of transduction of non-proliferating cells (MLV) and high vector particle immunogenicity (Ad). Lentiviral vectors overcome both problems and our cumulative preclinical studies using Feline Immunodeficiency Virus (FIV)-based lentiviral vectors resulted in persistent and therapeutic FVIII expression levels in the hemophilia mouse model. The next logical steps towards the initiation of clinical trials include a detailed investigation of vector particle interactions with the host's immune system as well as the testing of FIV-based FVIII therapy in a relevant large animal model-the hemophilia dog. Our goal is to generate FIV vectors coding for canine B domain-deleted FVIII (cFVIII) optimized for high expression levels. Optimization of cFVIII expression is modeled after successful modifications of the human FVIII and thus better mimics advanced human FVIII therapy while facilitating detection of serum FVIII protein levels and therapeutic benefit in the dog model. Our second goal is aimed at gaining a better understanding of possible immune responses to the FIV vector particle itself. To date, there has been no published investigation of innate or adaptive immune responses to lentiviral vector components in any animal system. A thorough understanding of the level or extent of any immune responses to FIV particles is an important safety and efficacy concern since FVIII gene transfer therapy likely needs to be re-administered after some time. The timeframe of this proposal allows the production of functional FIV-cFVIII vectors and the testing of first innate immune responses to FIV vector particles pseudotyped with three different envelopes. Future studies beyond the scope of the current proposal will be aimed at investigating FIV-based cFVIII gene transfer in the hemophilia dog while monitoring therapeutic expression levels and adaptive anti-FIV immune responses during repeat administrations.

描述（由申请方提供）：血友病A的当前标准治疗是静脉输注FVIII蛋白治疗，无论是急性发作还是出血发作期间。然而，由于可用性有限、成本高以及对静脉通路引起的血源性疾病的担忧，预防性治疗存在问题。使用病毒载体的基因转移提供了一种有吸引力的替代治疗方法，具有长期校正的潜力，因为仅5%的正常FVIII表达水平提供了实质性的临床益处。迄今为止，腺病毒（Ad）和肿瘤逆转录病毒（MLV）FVIII治疗的临床试验的成功受到缺乏非增殖细胞（MLV）转导和高载体颗粒免疫原性（Ad）的影响。慢病毒载体克服了这两个问题，并且我们使用基于猫免疫缺陷病毒（FIV）的慢病毒载体的累积临床前研究导致血友病小鼠模型中的持续和治疗性FVIII表达水平。临床试验启动的下一个合乎逻辑的步骤包括详细研究载体颗粒与宿主免疫系统的相互作用，以及在相关的大型动物模型-血友病犬中测试基于FIV的FVIII治疗。我们的目标是产生编码犬B结构域缺失的FVIII（cFVIII）的FIV载体，其针对高表达水平进行了优化。在成功修饰人FVIII后对cFVIII表达进行优化建模，从而更好地模拟高级人FVIII治疗，同时促进犬模型中血清FVIII蛋白水平和治疗获益的检测。我们的第二个目标是更好地了解对FIV载体颗粒本身可能的免疫应答。到目前为止，还没有发表的研究先天性或适应性免疫应答慢病毒载体成分在任何动物系统。全面了解对FIV颗粒的任何免疫应答的水平或程度是重要的安全性和有效性问题，因为FVIII基因转移治疗可能需要在一段时间后重新给药。该提议的时间框架允许产生功能性FIV-cFVIII载体并测试对用三种不同包膜假型化的FIV载体颗粒的第一先天免疫应答。超出当前提案范围的未来研究将旨在研究血友病犬中基于FIV的cFVIII基因转移，同时监测重复给药期间的治疗表达水平和适应性抗FIV免疫应答。