AN OPEN LABEL DOSE-ESCALATION STUDY OF A SELF COMPLEMENTARY AAV VECTOR FOR GENE THERAPY OF HAEMOPHILIA B

用于 B 型血友病基因治疗的自互补 AAV 载体的开放标签剂量递增研究

• 批准号: G0502121/1
• 负责人: Amit Nathwani
• 金额: $ 101.2万
• 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: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0502121%2F1
• 关键词: OPEN; LABEL; DOSE; ESCALATION; STUDY

In the proposed study we wish to test a new approach called gene therapy for the treatment of patients with haemophilia B. This inherited disorder in which life threatening bleeding occurs without trauma results from an absence or defect of a blood clotting protein called Factor IX (FIX) that arises due to mutations in the FIX 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 FIX gene so that normal FIX 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 (scAAV2/8-LP1-FIXco) which is highly efficient at transferring the normal FIX 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 and nonhuman primate models we have consistently achieved long-term expression of human FIX at levels that would be sufficient to prevent spontaneous life threatening bleeding in haemophilia B patients following a single injection of scAAV2/8-LP1-FIXco. The vector is simply infused into a peripheral vein, a highly convenient route of administration that dispenses with the need for surgical intervention for efficient transfer of the FIX gene to the liver. Based on these encouraging preclinical results we wish to evaluate this vector system in a small number of adults with severe haemophilia B. Eligible subjects, drawn from the worldwide pool of haemophiliacs, will receive explicit and detailed instructions about the risks and merits of this study prior to obtaining their consent for enrolment. Our primary aim is to establish the safety of peripheral vein administration of scAAV2/8-LP1-hFIXco over three different dosage levels. This study, which will be overseen by an international panel of medical experts, will involve a comprehensive plan of investigations to monitor safety, with particular emphasis on immune response to the virus and normal FIX protein. An additional objective is to determine the dose of vector that is required to achieve stable expression of human FIX at or above 5% of normal levels which would be sufficient to prevent spontaneous bleeding. 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，我们希望测试一种新的方法，称为基因治疗血友病B患者的治疗。这种遗传性疾病，其中在没有创伤的情况下发生危及生命的出血，这是由于缺乏或缺乏凝血蛋白（称为因子IX（FIX））而引起的，该凝血蛋白是由于FIX基因突变而引起的。因此，我们的基因治疗方法的目标是通过将FIX基因的正常拷贝转移到患者的肝脏来治疗疾病，以便患者自己的细胞可以持续产生正常的FIX蛋白。为此，我们开发了一种基于腺相关病毒的新型载体（scAAV 2/8-LP 1-FIXco），其在将正常FIX基因转移到肝脏（其天然合成位点）方面是高效的。重要的是，在病毒来源的基因转移载体中，AAV具有最好的安全性。在鼠和非人灵长类动物模型中，我们始终实现了人FIX的长期表达，其水平足以预防血友病B患者在单次注射scAAV 2/8-LP 1-FIXco后自发性危及生命的出血。载体简单地输注到外周静脉中，这是一种非常方便的给药途径，无需手术干预即可将FIX基因有效转移到肝脏。基于这些令人鼓舞的临床前结果，我们希望在少数重度血友病B成人中评价该载体系统。从全球血友病患者库中抽取的合格受试者在获得其入组同意书之前，将收到关于本研究风险和优点的明确和详细说明。我们的主要目的是确定在三种不同剂量水平上外周静脉施用scAAV 2/8-LP 1-hFIXco的安全性。这项研究将由一个国际医学专家小组监督，将涉及一项全面的调查计划，以监测安全性，特别强调对病毒和正常FIX蛋白的免疫反应。另一个目的是确定实现人FIX稳定表达（等于或高于正常水平的5%）所需的载体剂量，这足以预防自发性出血。我们的方法的成功可能会对多种危及生命的遗传性疾病产生显着影响，包括α-1抗胰蛋白酶缺乏症，溶酶体贮积症和尿素循环障碍。