Hemophilia A & B AAV vector delivery: factors VIII & IX

血友病A和B分别是由因子VIII和因子IX基因突变引起的。这些疾病是基因治疗的良好模型，因为相对直接的临床参数包括通过简单的血液测量来测量转基因产物和基于血浆水平的凝血变化。凝血活性低于1%的患者为非常严重的疾病，1%至5%为较中度的疾病，5%至20%为轻度疾病。广泛的循环因子具有良好的耐受性，使得基因治疗方法无需基因调控。肝脏是这两种凝血因子正常合成的器官。这使得它成为基因治疗方法的一个有吸引力的目标。虽然因子IX可以通过肌肉输送因子IX cDNA来治疗，但在肌肉中产生的因子VIII不能有效地分泌到血液中。此外，当直接比较肌肉和肝脏治疗FIX缺乏症的方法时，仍有许多问题尚未解决。这些因素包括抑制剂形成的相对风险，因子达到治疗水平与治疗水平的能力，以及达到给定血浆因子浓度水平所需的载体的相对剂量。重组AAV介导的肝脏基因转移在血友病的小型和大型动物模型中已被证明是安全有效的。该提案的目标是开展两项I期raav介导的肝脏临床试验，用于治疗血友病A和b。我们的主要目标将是解决这种方法在人类中的安全性。次要目标是证明血友病患者的表型改善。这里的试验设计也将为未来基于肝脏的临床试验提供有用的信息。

Hemophilias A and B are due to mutations in the factor VIII and IX genes, respectively. These diseases are good models for gene therapy because of the relatively straightforward clinical parameters that include measurement of the transgene product by simple blood measurements and changes in clotting based on plasma levels. Patients with less than 1% clotting activity have very severe disease, between 1 to 5% a more moderate disease, and 5 to 20% mild disease. A wide-range of circulating factor is well tolerated making gene regulation unnecessary for gene therapy approaches. The liver is the organ in which these two clotting factors are normally synthesized. This makes it an attractive target for gene therapy approaches. While factor IX may be treatable with muscle delivery of a factor IX cDNA, factor VIII produced in the muscle is not efficiently secreted in the bloodstream. Moreover, there are still a number of issues that are unresolved when the muscle and liver approaches for treating FIX deficiency are directly compared. These include the relative risks of inhibitor formation, the ability to reach therapeutic versus curative levels of factor, and the relative dose of vector required to achieve a given level of plasma factor concentration. Recombinant AAV- mediated liver gene transfer has proven to be safe as well as efficacious in both small and large animal models of hemophilia. The goal of the proposal is to develop two phase I rAAV-mediated liver-based clinical trials for the treatment of hemophilias A and B. Our primary goal will be address the safety of this approach in humans. The secondary goal will be demonstrated phenotypic improvement in patients with hemophilia. The trial design here will also provide useful information for future liver- based clinical trials.