High Katherine
University of Pennsylvania School of Medicine, Children's Hospital of Philadelphia, 19104, USA.
Genet Med. 2002 Nov-Dec;4(6 Suppl):56S-61S. doi: 10.1097/00125817-200211001-00012.
The goal of our work has been to establish an experimental basis for gene transfer as a method of treating hemophilia, an inherited bleeding disorder that results from the absence of functional factor VIII or factor IX. Using an adeno-associated viral vector derived from AAV serotype 2, we have shown in mice and in hemophilic dogs that we can achieve long-term expression (>3 years) of clotting factor at levels that would result in an improvement of clinical symptoms of the disease. A phase I trial of intramuscular injection of AAV-F.IX showed no evidence of local or systemic toxicity in any of the subjects. Muscle biopsies showed evidence for gene transfer and expression by polymerase chain reaction, Southern blot, and immunohistochemistry. We have also shown that AAV-F.IX can be delivered into the portal veins of hemophilic dogs and that this results in high circulating levels of factor IX, on the order of 5% to 14%, whereas delivery of similar doses to skeletal muscle results in factor levels of only 1% to 2%. Based on these results, a trial of AAV-mediated liver-directed gene transfer for hemophilia B has been proposed and is reviewed here.
我们工作的目标是为基因转移作为治疗血友病（一种因缺乏功能性凝血因子VIII或因子IX而导致的遗传性出血性疾病）的方法建立实验基础。使用源自AAV血清型2的腺相关病毒载体，我们已在小鼠和血友病犬中证明，我们能够使凝血因子长期表达（超过3年），其水平足以改善该疾病的临床症状。一项肌肉注射AAV - F.IX的I期试验表明，任何受试者均未出现局部或全身毒性迹象。肌肉活检通过聚合酶链反应、Southern印迹法和免疫组织化学显示了基因转移和表达的证据。我们还表明，AAV - F.IX可被递送至血友病犬的门静脉，这会导致因子IX的循环水平升高，约为5%至14%，而向骨骼肌递送相似剂量时，因子水平仅为1%至2%。基于这些结果，已提出一项针对B型血友病的AAV介导的肝靶向基因转移试验，并在此进行综述。
