Preclinical evaluation of rAAV encoding a novel highly expressed Factor VIII molecule for haemophilia A gene therapy

编码新型高表达因子 VIII 分子的 rAAV 用于 A 型血友病基因治疗的临床前评估

• 批准号: G0902219/1
• 负责人: Amit Nathwani
• 金额: $ 138.25万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0902219%2F1
• 关键词: Preclinical; evaluation; rAAV; encoding; novel

In the proposed study we wish to test a new approach called gene therapy for the treatment of patients with haemophilia A. This inherited disorder in which life threatening bleeding occurs without trauma results from an absence or defect of a blood clotting protein called Factor FVIII (FVIII) that arises due to mutations in the FVIIIX gene. The goal of our gene therapy approach, therefore, is to treat the disease by transferring to the patient?s liver, a normal copy of the FVIII gene so that normal FVIII protein can be continuously produced by the patient?s own cells. To this end we have developed a novel vector based on adeno-associated virus (rAAV8-HLP-codop-hFVIII) which is highly efficient at transferring the normal FVIII gene to the liver, its natural site of synthesis. Importantly, AAV has the best safety profile among gene transfer vectors of viral origin. In murine models we have consistently achieved long-term expression of human FVIII at levels that would be sufficient to prevent spontaneous life threatening bleeding in haemophilia A patients following a single injection of rAAV8-HLP-codop-hFVIII. Prior to evaluating this new vector in patients with haemophilia A, we have to establish its safety and efficacy to the rigorous standards required by the regulators using high quality clinical grade vector as opposed to research grade vector. This application is therefore designed to generate sufficient quantities of clinical grade rAAV8-HLP-codop-hFVIII vector and then carefully and critically evaluate its safety and efficacy in a context relevant to humans. The results of this study will be used to support the initiation of a clinical trial in patients with severe haemophilia A. Success with our approach could significantly impact on a wide variety of life threatening genetic disorders including alpha-1 antitrypsin deficiency, lysosomal storage and urea cycle disorders.

在拟议的研究中，我们希望测试一种称为基因疗法的新方法，用于治疗a型血友病患者。这种遗传性疾病，在没有创伤的情况下发生危及生命的出血，是由于FVIII基因突变引起的称为FVIII因子（FVIII）的凝血蛋白缺失或缺陷。因此，我们的基因治疗方法的目标是通过转移到患者身上来治疗疾病。在患者的肝脏中，正常的FVIII基因拷贝使正常的FVIII蛋白可以持续产生。S自己的细胞。为此，我们开发了一种基于腺相关病毒（raav8 - hlp - codopa - hfviii）的新型载体，该载体可以高效地将正常的FVIII基因转移到肝脏（其天然合成位点）。重要的是，在病毒来源的基因转移载体中，AAV具有最佳的安全性。在小鼠模型中，我们一致地实现了人类FVIII的长期表达，其水平足以防止血友病A患者在单次注射raav8 - hlp - codopa - hfviii后自发性危及生命的出血。在对这种新载体在A型血友病患者中进行评估之前，我们必须使用高质量的临床级载体而不是研究级载体，根据监管机构要求的严格标准确定其安全性和有效性。因此，该应用程序旨在产生足够数量的临床级raav8 - hlp - codopa - hfviii载体，然后在与人类相关的环境中仔细和批判性地评估其安全性和有效性。这项研究的结果将用于支持在严重血友病a患者中开展临床试验。我们的方法的成功可能会对多种危及生命的遗传疾病产生重大影响，包括α -1抗胰蛋白酶缺乏症、溶酶体储存和尿素循环障碍。