NHLBI MAINTENANCE OF CANINE MODELS OF HUMAN BLEEDING DISORDERS

该N01合同的目的是生产和维护以下遗传性出血性疾病犬模型，用于独立和合作的科学研究：分别具有和不具有FVIII和FIX抑制抗体的血友病A和血友病B；血管性血友病；FVII-deficiency;以及格兰兹曼凝血症。从1947年NIH/NHLBI的R01开始，肯尼斯·m·布林克豪斯博士和他的同事们识别了这些狗，并证明：(1)它们反映了各自人类疾病中存在的严重出血表型；(2)对成功的转化研究具有很强的预测准确性1999年，Brinkhous博士R01的审稿人认为这些狗是一种重要的国家资源，应该提供给研究界，NHLBI的支持也过渡到R24 （T.C. Nichols， PI）。我们现在申请将这个殖民地的支持过渡到N01合同。自1999年以来，我们已经与30多个研究团队合作生产了出血犬和正常犬，其中大多数得到了NHLBI的支持，并在超过95篇同行评议的出版物（1-96）和会议论文集（97-102）中报道了这项工作，其中一些被选为编辑评审。最近，至少5项针对血友病B和2项针对血友病A的人类基因治疗试验中使用的载体、6种新的重组抗血友病蛋白以及针对VWD的重组血管性血友病因子（VWF）和IL-1120在这些狗身上进行了临床试验前的测试。在所有情况下，结果预测了安全性、有效性和药物剂量反应。这些动物的主要好处是加速了凝血和止血研究中可转化的发现科学，并为安全有效地将新疗法引入临床实践提供了科学基础。

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.