Immune Tolerance to Factor IX in Hemophilia B

描述(申请人提供)：血友病B是一种遗传性疾病 由于凝血因子IX的缺乏。血友病B的现代治疗方法 患者正在接受蛋白质治疗，目前正在进行一项临床试验 基因治疗方法。在目前的蛋白质疗法中，有一小部分(3 %)的患者产生中和FIX的抑制性抗体 蛋白质活性使治疗无效。试图消除 大剂量FIX或免疫抑制法产生的抑制性抗体 治疗并不总是成功的。我们假设有效的免疫力 耐受性策略将使目前的血友病B疗法成为 所有患者均获得成功。在这个提案中，我们假设血友病B 小鼠口服FIX可耐受FIX。在第一个目标中，我们 将确定是否可以在新生儿或婴儿中实现口服耐受性 成年血友病B小鼠。具体地说，我们将产生小鼠乳清酸性 蛋白启动子-人凝血因子IX转基因小鼠及其表达水平的研究 老鼠奶中的hF.IX。这些转基因小鼠将被用于确定 摄入mWAP-hF.IX雌性小鼠的乳汁是否能够耐受 新生血友病B鼠至hF.IX成年Hem B小鼠将在 他们的水来确定给成年的Hem B小鼠喂食抗原是否能够 诱导耐受性。在第二个目标中，我们将确定对人类的宽容 FIX可以通过FIX在小鼠肠上皮细胞中的持续表达来实现 血友病B组小鼠。这将证明成年的Hem B小鼠是否可以耐受 在肠道组织中修复并持续表达F.IX可能有助于 诱导耐受性。

DESCRIPTION (provided by applicant): Hemophilia B is a genetic disease caused by a deficiency of clotting factor IX. Current therapy for Hemophilia B patients is protein therapy and clinical trials are currently underway for a gene therapy approach. With the current protein therapy, a small percentage (3 percent) of patients develop inhibitory antibodies that neutralize the F.IX protein activity rendering treatment ineffective. Attempts to eliminate inhibitory antibodies by infusing high doses of F.IX or by immunosuppressive treatment are not always successful. We hypothesize that effective immune tolerance strategies will enable current therapies for Hemophilia B to be successful for all patients. In this proposal we hypothesize that Hemophilia B mice can be tolerized to FIX by oral administration of FIX. In the first aim we will determine if oral tolerance to human FIX can be achieved in neonatal or adult Hemophilia B mice. Specifically, we will generate mouse whey acidic protein promoter-human Factor IX transgenic mice and characterize the levels of hF.IX in the mouse milk. These transgenic mice will be used to determine whether ingestion of milk from the mWAP-hF.IX female mice is able to tolerize the newborn Hemophilia B mice to hF.IX. Adult Hem B mice will be fed hFIX in their water to determine if feeding the antigen to adult Hem B mice is able to induce tolerance. In the second aim we will determine if tolerance to human F.IX can be achieved by continuous expression of FIX in gut epithelium of Hemophilia B mice. This will demonstrate if adult Hem B mice can be tolerized to FiX and if continuous expression of F.IX in gut tissue may facilitate the induction of tolerance.