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

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b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FIX基因突变引起的一种称为IX因子（FIX）的凝血蛋白缺失或缺陷。因此，基因治疗的目标是，将正常的FIX基因拷贝移植到患者的肝脏中，使患者自身细胞持续产生正常的FIX蛋白。为此，我们开发了一种基于腺相关病毒（scAAV2/8-LP1-FIXco）的新型载体，该载体可以高效地将正常的FIX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。在小鼠和非人灵长类动物模型中，我们一致地实现了人类FIX的长期表达水平，足以防止血友病B患者在单次注射scAAV2/8-LP1-FIXco后自发性危及生命的出血。载体只需注入外周静脉，这是一种非常方便的给药途径，无需手术干预即可将FIX基因有效地转移到肝脏。基于这些令人鼓舞的临床前结果，我们希望在少数患有严重b型血友病的成人中评估该载体系统。从全球血友病患者中选取符合条件的受试者，在获得他们的入组同意之前，将收到关于该研究风险和优点的明确和详细的说明。我们的主要目的是确定三种不同剂量水平下scAAV2/8-LP1-hFIXco外周静脉给药的安全性。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。另一个目标是确定使人FIX稳定表达在正常水平的5%或以上所需的载体剂量，这足以防止自发性出血。我们的方法的成功可以显著影响各种威胁生命的遗传疾病，包括α -1抗胰蛋白酶缺乏症，溶酶体储存和尿素循环障碍。

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.