Gene Therapy for Hemophilia

描述（由申请人提供）：这是名为“血友病基因治疗”的项目项目资助（PPG）的第二次竞争性续期申请。PPG由3个项目和3个核心组成。这三个项目都是从以前的PPG继续进行的。项目1由Valder Arruda博士指导，将利用一种新颖的因子(f)。IX变种（F.IX Padua, R338L），其活性是野生型F.IX的10倍。Arruda博士将研究F.IX Padua在犬血友病模型中的功效和潜在副作用，并研究F.IX Padua增加特定活性的分子基础。项目2，由Dr. Katherine High指导，将检验在血友病犬血管内将aavfvia载体传递到骨骼肌后持续表达VIla因子的安全性和有效性；她还将开发一种可由强力霉素调节的诱导型病毒载体。项目3，由l /lortimer Poncz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fviii形成血栓的细节，并制定策略，以避免观察到的凝块不稳定，同时在血友病A小鼠和狗的抑制剂存在下保持血小板fviii活性。这三个项目将得到三个核心的支持：核心A，行政核心，将支持和协调小组之间的科学互动。Core B，即Vector Core，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（UNC-Chapel Hill）的大型动物模型中心（Core C）将为血友病犬提供接触途径，并将提供凝血测试和这些动物体内凝血模型的专业知识。该PPG提出了三个高度创新的项目，以推进遗传性出血性疾病患者的护理，包括血友病A、血友病B和fviii或fix抑制剂患者。这三个项目研究了利用骨骼肌或造血细胞作为基因转移靶点的治疗策略，因此对于那些由病毒性肝炎引起的肝脏疾病（包括很大一部分患有严重血友病的成年人）的临床转化也是可行的。这三个项目都是高度互动的，并且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.