Gene Therapy for Hemophilia

描述(由申请人提供)：这是名为血友病基因治疗的计划项目拨款(PPG)的第二次竞争性续签申请。PPG由3个项目和3个核心组成。所有这三个项目都是从上一个PPG继续进行的。由瓦尔德·阿鲁达博士执导的项目1将利用一个新的因素(F)。Arruda博士将研究F.IX Padua在犬血友病8模型中的疗效和潜在的副作用，并研究F.IX Padua比活性增加的分子基础。由Katherine High博士指导的项目2将检验AAVFVIIa载体在血友病狗的血管内输送到骨骼肌后持续表达Vila因子的安全性和有效性；她还将开发一种可受多西环素调节的可诱导Vila载体。项目3由L博士和洛蒂默·庞茨博士指导，将继续他在上一个资助期的成功工作，以了解血小板输送的F.VIII形成血栓的细节，并开发避免观察到的凝块不稳定的策略，同时在血友病A小鼠和狗中在抑制物存在的情况下保持血小板F.VIII的活性。这3个项目将得到三个核心的支持：核心A，即行政核心，将支持和协调小组之间的科学互动。核心B，即媒介核心，将为研究人员提供研究级AAV和慢病毒载体。最后，北卡罗来纳大学教堂山分校的大型动物模型核心C将为血友病狗提供通道，并将提供这些动物的凝血测试和体内凝血模型方面的专业知识。PPG提出了三个高度创新的项目，以推进对遗传性出血疾病患者的护理，包括血友病A、血友病B和F.VIII或F.IX的抑制剂患者。这三个项目研究利用骨骼肌或造血细胞作为基因转移目标的治疗策略，因此即使对于病毒性肝炎引起的肝病患者(包括很大一部分患有严重血友病的成年人)，临床翻译也是可行的。这些项目互动性很强，这三个项目都充分利用了拟议的核心。

DESCRIPTION (provided by applicant): This is the second competitive renewal application for a Program Project Grant (PPG) entitled Gene Therapy for Hemophilia. The PPG consists of 3 projects and 3 cores. All three projects are continued from the previous PPG. Project 1, directed by Dr. Valder Arruda, will take advantage of a novel Factor (F.) IX variant (F.IX Padua, R338L) that has 10-fold the activity of wild type F.IX. Dr. Arruda will study F.IX Padua's efficacy and potential side-effects in the canine hemophilia 8 models as well as study the molecular basis for F.IX Padua's increased specific activity. Project 2, directed by Dr. Katherine High, will examine the safety and efficacy of continuous expression of Factor VIla after intravascular delivery to skeletal muscle of an AAVFVIIa vector in hemophilic dogs; she will also develop an inducible Vila vector that can be regulated by doxycycline. Project 3, directed by Dr. l\/lortimer Poncz, will continue his successful work of the previous funding period to understand the details of thrombus development by platelet-delivered F.VIII and to develop strategies to avoid observed clot instability while retaining platelet F.VIII activity in the presence of inhibitors in both hemophilia A mice and dogs. These 3 projects will be supported by three cores: Core A, the Administrative Core, will support and co-ordinate scientific interactions among the group. Core B, the Vector Core, will provide research grade AAV and lentiviral vectors for the investigators. Finally, Core C, the Large Animal Models Core at UNC-Chapel Hill, will provide access to hemophilic dogs and will provide expertise in coagulation testing and in vivo clotting models in these animals. This PPG presents three highly innovative projects to advance the care of patients with inherited bleeding disorders, including hemophilia A, hemophilia B, and patients with inhibitors to F.VIII or F.IX. The three projects investigate therapeutic strategies that utilize skeletal muscle or hematopoietic cells as targets for gene transfer, and thus are feasible for clinical translation even for those with liver disease due to viral hepatitis, which includes a large fraction of adults with severe hemophilia. The projects are highly interactive, and all three take full advantage of the proposed cores.