Nichols Timothy C, Whitford Margaret H, Arruda Valder R, Stedman Hansell H, Kay Mark A, High Katherine A
1 Francis Owen Blood Research Laboratory, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill , Chapel Hill, NC 27516.
Hum Gene Ther Clin Dev. 2015 Mar;26(1):5-14. doi: 10.1089/humc.2014.153. Epub 2015 Feb 12.
Preclinical testing of new therapeutic strategies in relevant animal models is an essential part of drug development. The choice of animal models of disease that are used in these studies is driven by the strength of the translational data for informing about safety, efficacy, and success or failure of human clinical trials. Hemophilia B is a monogenic, X-linked, inherited bleeding disorder that results from absent or dysfunctional coagulation factor IX (FIX). Regarding preclinical studies of adeno-associated virus (AAV)-mediated gene therapy for hemophilia B, dogs with severe hemophilia B (<1% FIX) provide well-characterized phenotypes and genotypes in which a species-specific transgene can be expressed in a mixed genetic background. Correction of the hemophilic coagulopathy by sustained expression of FIX, reduction of bleeding events, and a comprehensive assessment of the humoral and cell-mediated immune responses to the expressed transgene and recombinant AAV vector are all feasible end points in these dogs. This review compares the preclinical studies of AAV vectors used to treat dogs with hemophilia B with the results obtained in subsequent human clinical trials using muscle- and liver-based approaches.
在相关动物模型中对新治疗策略进行临床前测试是药物开发的重要组成部分。这些研究中所使用的疾病动物模型的选择，是由用于预测人类临床试验安全性、疗效及成败的转化数据的力度所驱动的。乙型血友病是一种单基因、X连锁的遗传性出血性疾病，由凝血因子IX（FIX）缺失或功能异常所致。关于腺相关病毒（AAV）介导的乙型血友病基因治疗的临床前研究，患有严重乙型血友病（FIX<1%）的犬提供了特征明确的表型和基因型，其中一种物种特异性转基因可在混合遗传背景中表达。通过FIX的持续表达纠正血友病性凝血病、减少出血事件，以及对表达的转基因和重组AAV载体的体液和细胞介导免疫反应进行全面评估，在这些犬中都是可行的终点。本综述比较了用于治疗乙型血友病犬的AAV载体的临床前研究与随后使用基于肌肉和肝脏的方法进行的人类临床试验所获得的结果。
