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（由申请人提供）：血友病A的当前护理标准是静脉内FVIII蛋白输注的治疗，无论是预防性还是在出血发作期间。然而，由于静脉通路导致的血液传播疾病的可用性有限，成本高昂和关注，预防性治疗是有问题的。使用病毒载体转移基因转移提供了一种有吸引力的替代治疗方法，具有长期矫正的潜力，因为只有5％的正常FVIII表达水平提供了实质性的临床益处。迄今为止，由于缺乏非增殖细胞（MLV）和高载体颗粒免疫原性（AD）的转导，通过ADENO（AD）和癌症（MLV）FVIII治疗的临床试验成功受到了损害。使用猫免疫缺陷病毒（FIV）基于基于的慢病毒载体，慢病毒载体克服了问题和我们的累积临床前研究，从而在血友病小鼠模型中导致持久和治疗性的FVIII表达水平。启动临床试验的下一个逻辑步骤包括对载体颗粒与宿主免疫系统的相互作用的详细研究，以及在相关的大型动物模型 - 血友病犬中对基于FIV的FVIII治疗的测试。我们的目标是生成针对高表达水平优化的犬B域删除的FVIII（CFVIII）的FIV载体。 CFVIII表达的优化是在成功修饰人FVIII的情况下建模的，从而更好地模拟了先进的人FVIII治疗，同时促进了狗模型中血清FVIII蛋白水平和治疗益处的检测。我们的第二个目标旨在更好地了解对FIV矢量粒子本身可能的免疫反应。迄今为止，还没有对任何动物系统中对慢病毒载体成分的先天或适应性免疫反应进行的发表调查。对FIV颗粒的任何免疫反应的水平或程度的全面理解是重要的安全性和功效，因为FVIII基因转移疗法可能需要在一段时间后重新管理。该提案的时间范围允许生产功能性的FIV-CFVIII载体，并测试对FIV载体颗粒的首次先天免疫反应，以三种不同的信封进行伪型。未来的研究超出了当前建议的范围，旨在研究基于FIV的CFVIII基因转移，同时监测重复施用期间的治疗表达水平和适应性抗FIV免疫反应。