Bone Marrow-Derived Stem Cell Therapy of Hemophilia A

描述(由申请人提供)：血友病A是一种先天性出血性疾病，由影响血浆蛋白的基因突变引起，称为第八因子(FVIII)，其功能是促进血液凝固。血友病A的最新治疗包括频繁静脉输注含有FVIII的产品。目前治疗血友病的限制是1)获得FVIII产品，2)FVIII产品的成本，3)对FVIII的免疫反应阻碍了治疗效果，4)由于个别关节反复出血而导致的关节疾病的发病率。由于为患者提供临床益处所需的FVIII的数量有限，血友病A是一种基于细胞和基因治疗的有吸引力的疾病。血友病A的基因治疗已经进行了三个I期临床试验，这就证明了这一点。此外，已经证明，将非血友病A患者的肝脏移植到血友病A患者身上可以治愈这种疾病。然而，由于器官短缺和移植相关的风险，通过原位肝移植治疗血友病是不现实的。一些研究人员现在已经证明，骨髓来源的细胞具有重新填充肝脏组织并表达肝脏特异性蛋白的能力。因此，骨髓来源的干细胞有可能成为治疗血友病A的一种安全有效的方法。我们建议评估骨髓来源的干细胞作为治疗血友病A的一种选择的潜力，并利用血友病A的小鼠模型鉴定合成FVIII的供体细胞系。所建议的研究结果将1)有助于确定不同类型的肝细胞在FVIII生物合成中所起的相对作用，2)促进基于细胞和基因转移的治疗血友病A的新疗法的设计。

DESCRIPTION (provided by applicant): Hemophilia A is a congenital bleeding disorder caused by genetic mutations affecting a plasma protein, termed factor VIII (fVIII), whose function is to facilitate blood clotting. State of the art treatment of hemophilia A consists of frequent intravenous infusion of fVIII containing products. The current limitations to treating hemophilia are 1) access to fVIII products, 2) the cost of fVIII products, 3) the development of immune responses against fVIII that block treatment efficacy and 4) morbidity due to joint disease resulting from repeated bleeding into individual joints. Due to the limited amount of fVIII needed to provide clinical benefit to the patient, hemophilia A is an attractive disease for cell and gene-based therapy. This is evidenced by the fact that there have been three phase I clinical trials for gene therapy of hemophilia A conducted. In addition, it has been demonstrated that liver transplantation from a non-hemophilia A individual into a hemophilia A patient cures the disease. However due to organ shortage and transplant associated risks, treatment of hemophilia by orthotopic liver transplantation is not practical. Several investigators now have demonstrated that bone marrow-derived cells have the ability to repopulate liver tissue and express liver-specific proteins. Therefore, bone marrow-derived stem cells potentially could serve as a safe and effective therapeutic for hemophilia A. We, propose to evaluate the potential for bone marrow-derived stem cells as a treatment option for hemophilia A and identify the donor cell lineages that synthesize fVIII using a murine model of hemophilia A. The results obtained from the proposed studies should 1) aid in defining the relative roles different liver cell types play in fVIII biosynthesis and 2) facilitate the design of novel cellular and gene transfer-based therapies for hemophilia A.