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NHLBI MAINTENANCE OF CANINE MODELS OF HUMAN BLEEDING DISORDERS

NHLBI 人类出血性疾病犬模型的维护

基本信息

批准号：
10499861
负责人：
TIMOTHY NICHOLS
金额：
$ 142.25万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2022-09-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10499861
关键词：
Animal Experimentation Animal Model Animals Antibodies Basic Science Biological Assay Blood Blood Coagulation Disorders Blood Platelets Blood coagulation Blood donor Breeding Canada Canis familiaris Caring Clinical Clinical Trials Coagulation Process Collaborations Communities Contracts Defect Deletion Mutation Disease Dose Ensure Erythrocytes Exons Experimental Designs F8 gene Fresh Frozen Plasmas Funding Gene Transfer Gene therapy trial Genes Genetic Grant Hemophilia A Hemophilia B Hemorrhage Hemostatic Agents Hemostatic function Human Human Resources Inherited Introns Investigation Laboratory Research Maintenance Mentors Modeling Molecular Monoclonal Antibody R24 National Heart, Lung, and Blood Institute Patients Peer Review Performance Pharmaceutical Preparations Phenotype Plasma Production Proteins Recombinants Reporting Research Research Personnel Research Project Grants Resources Safety Science Services Site Support Contracts Technical Expertise Testing Therapeutic Thrombasthenia Thromboplastin Training Translational Research United States National Institutes of Health Whole Blood Work animal care blood product clinical practice cost cost effective design editorial experience gain of function human model inhibitor/antagonist inter-institutional novel novel therapeutics null mutation research study response symposium vector von Willebrand Disease von Willebrand Factor

项目摘要

The purpose of this N01 contract is to produce and maintain the following dog models of inherited bleeding disorders for independent and collaborative scientific investigations: hemophilia A and hemophilia B with and without inhibitory antibodies to FVIII and FIX, respectively; von Willebrand disease (VWD); FVII-deficiency; and Glanzmann’s Thrombasthenia. Beginning in 1947 with an R01 from NIH/NHLBI, Dr. Kenneth M. Brinkhous and colleagues identified these dogs and demonstrated that (1) they mirror the severe bleeder phenotype present in the respective human disorder and (2) have a strong predictive accuracy for successful translational research.1 In 1999, the reviewers of Dr. Brinkhous’ R01 judged these dogs to be an important national resource that should be made available to the research community and NHLBI support was transitioned to an R24 (T.C. Nichols, PI). We are now applying to transition support of this colony to this N01 contract. Since 1999, we have produced bleeder and normal dogs that have been used in collaborations with over 30 teams of investigators, most with NHLBI support, and the work has been reported in over 95 peer-reviewed publications1-96 and Conference Proceedings97-102, several of which were selected for editorial review. Recently, vectors used in at least 5 human gene therapy trials for hemophilia B and 2 for hemophilia A, six new recombinant anti-hemophilic proteins, and recombinant von Willebrand factor (VWF)and IL-1120 for VWD have been tested in these dogs prior to clinical trials. In all cases, the results predicted safety, efficacy, and drug dose responses. The primary benefits of these animals have been to accelerate translatable discovery science in coagulation and hemostasis research and to produce the scientific basis for the safe and efficacious introduction of novel therapeutics into clinical practice. Considerable progress has been made over the past 7 decades in understanding the basic science of blood coagulation and hemostasis and in developing new clinical approaches to inherited bleeding disorders. Yet, there are persistent limitations in therapeutic options for people with VWD and hemophilia, especially those with inhibitors.

本N 01合同的目的是生产和维护以下遗传性出血性疾病的犬模型，用于独立和合作的科学研究：分别使用和不使用FVIII和FIX抑制性抗体的血友病A和血友病B;血管性血友病（VWD）; FVIII缺乏症;和Glanzmann血栓无力症。从1947年开始，Kenneth M. Brinkhous及其同事鉴定了这些狗，并证明（1）它们反映了相应人类疾病中存在的严重出血表型，（2）对于成功的转化研究具有很强的预测准确性。Brinkhous博士的R 01的评审员认为这些狗是一种重要的国家资源，应该提供给研究界，NHLBI的支持已经过渡到转换为R24（TC Nichols，PI）。我们现在正在申请将这个殖民地的支持过渡到这个N 01合同。自1999年以来，我们已经生产了出血犬和正常犬，这些犬已与30多个研究团队合作使用，其中大多数都得到了NHLBI的支持，这项工作已在超过95个同行评审的出版物1 -96和会议论文集97 -102中报道，其中一些被选中进行编辑审查。最近，在临床试验之前，已经在这些狗中测试了用于血友病B的至少5个人类基因治疗试验和用于血友病A的2个人类基因治疗试验的载体、六种新的重组抗血友病蛋白以及用于VWD的重组血管性血友病因子（VWF）和IL-1120。在所有情况下，结果预测了安全性、有效性和药物剂量反应。这些动物的主要受益是加速凝血和止血研究中的可转化发现科学，并为安全有效地将新型治疗方法引入临床实践提供科学依据。在过去的70年里，在了解血液凝固和止血的基础科学以及开发治疗遗传性出血性疾病的新临床方法方面取得了相当大的进展。然而，VWD和血友病患者的治疗选择存在持续的局限性，特别是那些具有抑制剂的患者。