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（称为因子VIII（fVIII））的基因突变引起，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FVIII的产品。目前治疗血友病的局限性是1）获得fVIII产品，2）fVIII产品的成本，3）针对fVIII的免疫应答的发展阻碍了治疗疗效，以及4）由于单个关节反复出血导致的关节疾病导致的发病率。由于为患者提供临床获益所需的fVIII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。事实证明，已经进行了三次血友病A基因治疗的I期临床试验。此外，已经证明，从非血友病A个体到血友病A患者的肝移植治愈了该疾病。然而，由于器官短缺和移植相关的风险，原位肝移植治疗血友病是不切实际的。一些研究人员现在已经证明，骨髓来源的细胞有能力重新填充肝组织和表达肝脏特异性蛋白质。因此，骨髓源性干细胞有可能成为血友病A安全有效的治疗药物。我们建议评估骨髓源性干细胞作为血友病A治疗选择的潜力，并使用血友病A小鼠模型鉴定合成fVIII的供体细胞系。从拟定研究中获得的结果应1）有助于确定不同肝细胞类型在fVIII生物合成中的相对作用，2）促进血友病A新型细胞和基因转移治疗的设计。

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.