Long-term safety and efficacy of factor IX gene therapy in hemophilia B.
Long-term safety and efficacy of factor IX gene therapy in hemophilia B.
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DOI：
10.1056/nejmoa1407309
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发表时间：
2014-11-20
期刊：
影响因子：
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通讯作者：
Davidoff AM
中科院分区：
文献类型：
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作者：
Nathwani AC;Reiss UM;Tuddenham EG;Rosales C;Chowdary P;McIntosh J;Della Peruta M;Lheriteau E;Patel N;Raj D;Riddell A;Pie J;Rangarajan S;Bevan D;Recht M;Shen YM;Halka KG;Basner-Tschakarjan E;Mingozzi F;High KA;Allay J;Kay MA;Ng CY;Zhou J;Cancio M;Morton CL;Gray JT;Srivastava D;Nienhuis AW;Davidoff AM
在重度血友病B患者中，由新型自身互补腺相关病毒血清型8（AAV 8）载体介导的基因治疗已显示可提高因子IX水平长达16个月。我们想确定转基因表达的持久性，载体剂量-反应关系，以及持续或晚期毒性的水平。我们在10例重度血友病B患者中评价了转基因表达的稳定性和长期安全性：6例患者已入组初始1期剂量递增试验，其中2例患者分别接受低、中或高剂量，另外4例患者接受高剂量（2×1012个载体基因组/千克体重）。患者随后接受了广泛的临床和实验室监测。在所有10例重度血友病B患者中，单次静脉输注载体导致循环因子IX呈剂量依赖性增加，在中位3.2年内达到正常值的1 - 6%，观察仍在进行中。在高剂量组中，在所有6例患者中观察到因子IX水平一致升高至平均值（±SD）5.1±1.7%，这导致出血事件和预防性因子IX浓缩物使用减少90%以上。高剂量组6例患者中有4例在第7周至第10周之间出现平均丙氨酸氨基转移酶水平一过性升高至86 IU/L（范围：36 - 202），但在泼尼松龙治疗后中位5天（范围：2 - 35）内消退。在10名重度血友病B患者中，输注单剂量的AAV 8载体导致与临床改善相关的长期治疗因子IX表达。在长达3年的随访期内，未报告治疗的晚期毒性作用。（由国家心肺血液研究所和其他机构资助; ClinicalTrials.gov编号，NCT 00979238。
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. 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. 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. 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. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238.)