英国研究人员观察了10例接受AAV8载体治疗的重型B型血友病病人,发现循环中的IX因子水平出现剂量依赖的增高,到达正常值的1-6%,持续3.2年,出血和预防性使用IX因子浓缩物均减少;同时未见晚期毒性效应出现。

—2014年11月20日《新英格兰医学杂志》

中文译文


 

【题目】因子IX基因治疗B型血友病的长期安全性和有效性
【译文】
背景:在重型B型血友病病人中,通过一种新的自身互补的8型腺病毒(AAV8)载体介导的基因治疗,已经显示出在16个月之后可以增加IX因子的水平。我们旨在确定转基因表达的持续性、载体的剂量-效应关系,以及持续的或后期的毒性水平。
方法:我们在10个重型B型血友病病人中,评估了转基因表达的稳定性和长期安全性。其中6人已参与了最初的1期剂量递增试验,各有2人接受低、中、高剂量治疗;4个新加入的病人接受高剂量治疗(2×1012载体基因组/kg体重)。随后病人接受了大量的临床和实验室监测。
结果:全部10个重型B型血友病病人均接受单次静脉注射载体,循环中的IX因子水平出现剂量依赖的增高,到达正常值的1-6%,持续3.2年,并在观察过程中持续存在。在高剂量组,6个病人均观察到IX因子水平持续增高,平均数(±SD)为5.1±1.7%,使出血和预防性使用IX因子浓缩物均减少了90%以上。在高剂量组的6个病人中,在第7周到第10周期间,有4个病人出现一过性的谷丙转氨酶水平增高,均值为86 IU/L(范围36-202 IU/L),在接受类固醇治疗超过5天(中位数;范围2-35天)后恢复正常。
结论:在10个重型B型血友病病人中,单剂量注射AAV8载体所致长期治疗性的IX因子表达与临床表现改观有关。随访到3年,治疗组未见晚期毒性效应出现。

 

英文原文


 

[Title] Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B

[Authors] Amit C. Nathwani, M.B., Ch.B., Ph.D., Ulreke M. Reiss, M.D., Edward G.D. Tuddenham, M.B., B.S., Cecilia Rosales, Ph.D., Pratima Chowdary, M.B., B.S., Jenny McIntosh, Ph.D., et al.
[Abstract]
BACKGROUND: In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose–response relationship, and the level of persistent or late toxicity.
METHODS: We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×1012 vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring.
RESULTS: A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment.
CONCLUSIONS: In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported.

 

原文网址:


http://www.nejm.org/doi/full/10.1056/NEJMoa1407309

 

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