Animal Core for Gene Therapy of Hemophilia

血友病基因治疗的动物核心

基本信息

批准号：
8185350
负责人：
Timothy Charles Nichols
金额：
$ 34.63万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8185350
关键词：
Acoustics Address Adverse effects Animal Model Animals Antibodies Antibody Formation Attention Biodistribution Biopsy Birth Blood Bone Marrow Aspiration Breeding Canis familiaris Cell Line Cultured Cells Cyclophosphamide DNA Dose Exhibits Extravasation Faculty Female Funding Gene Expression Gene Expression Profiling Gene Transfer Genes Genotype Grant Hemophilia A Hemophilia B Hemorrhage Hemorrhagic Disorders Hemostatic Agents Hepatic artery Histopathology Housing Human Human Resources Image Immunosuppression Investigation Joints Laboratory Research Maintenance Methods Modeling Modus Molecular Monitor Monoclonal Antibody R24 National Heart, Lung, and Blood Institute North Carolina Organ Patients Pharmacopoeias Plasma Portal vein structure Pregnancy Procedures Program Research Project Grants Prophylactic treatment Protocols documentation Publications RNA Radiation Recombinants Records Relative (related person)Research Personnel Resources Severities Specimen Testing Tissues Toxic effect Training Transfusion Ultrasonography Universities artery infusion base experience gene therapy laboratory facility member novel prevention service programs research study response success tool transgene expression vector

项目摘要

The purpose of this Animal Core is to perform and monitor gene therapy studies in dog models of human hemophilia A, hemophilia B, and F.VII deficiency for the scientific investigations proposed in Projects 1 through 3. To date, successful gene therapy in hemophilic dogs has resulted in long-term (from 1 to > 10 years) expression of plasma factors Vlll (F.VIII), IX (F.IX), and F.Vila and many of these dogs have exhibited a lower toxicity issues have been detected to date. These studies have also highlighted the limitations in gene therapy including low levels of transgene expression, dose thresholds for inhibitory antibody formation, and the relative paucity of strategies for hemophilia patients with inhibitory antibodies. These limitations and other critical issues in hemophilia gene therapy are addressed in this PPG. In the next grant period, a novel ultrasound based test entitled "Acoustic Radiation Force Impulse" imaging will be validated as a hemostatic challenge and used as an additional tool to monitor hemostatic efficacy of the various gene transfer protocols. Please note that this Core will support the gene transfer experiments and the experimental animals (those receiving gene transfer) that will be housed and monitored at the Francis Owen Blood Research Laboratory (FOBRL) at the University of North Carolina at Chapel Hill. The non-experimental animals (breeders, substrate and normal plasma donors, etc.) will largely be supported by an NHLBI-funded Resource Grant (R24-HL63098) entitled "Maintenance of Animal Models of Hemophilia and VWD," Timothy C. Nichols P.l.

该动物核心的目的是在人类血友病A，血友病B和F.VII缺乏症的狗模型中进行和监测基因疗法研究，以在项目1到3中提出的科学研究。迄今为止，已经发现了血浆因子VLLL（F.VIII），IX（F.IX）和F.Vila和许多这些狗的表达表现出较低的毒性问题。这些研究还强调了基因疗法的局限性，包括低水平的转基因表达，抑制性抗体形成的剂量阈值以及对抑制性抗体的血友病患者策略的相对缺乏。在此PPG中解决了血友病基因疗法中的这些局限性和其他关键问题。在下一个赠款期间，一个新型的基于超声的测试名为“声学” 辐射力冲动“成像将被验证为止血挑战，并用作监测各种基因转移方案的止血疗效的附加工具。请注意，该核心将支持基因转移实验和将在北卡罗来纳大学教堂山分校的弗朗西斯·欧文血液研究实验室（FOBRL）中安置和监测的实验动物（接受基因转移的动物）。非实验性动物（育种者，底物和正常的血浆供体等）将在很大程度上得到NHLBI资助的资源赠款（R24-HL63098）的支持，标题为“维持血友病和VWD动物模型，” Timothy C. Nichols P.L.