Adenovirus-associated virus vector-mediated gene transfer in hemophilia B.
Adenovirus-associated virus vector-mediated gene transfer in hemophilia B.
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DOI：
10.1056/nejmoa1108046
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发表时间：
2011-12-22
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;Tuddenham EG;Rangarajan S;Rosales C;McIntosh J;Linch DC;Chowdary P;Riddell A;Pie AJ;Harrington C;O'Beirne J;Smith K;Pasi J;Glader B;Rustagi P;Ng CY;Kay MA;Zhou J;Spence Y;Morton CL;Allay J;Coleman J;Sleep S;Cunningham JM;Srivastava D;Basner-Tschakarjan E;Mingozzi F;High KA;Gray JT;Reiss UM;Nienhuis AW;Davidoff AM
血友病B是一种X连锁疾病，非常适合进行基因治疗。我们调查了一种新的基因疗法在这种疾病患者中的使用。我们将表达密码子优化的人凝血因子IX(FIX)转基因基因(scAAV2/8-LP1-hFIXco)的血清型8假型、自身互补型腺病毒相关病毒(AAV)载体(scAAV2/8-LP1-hFIXco)单剂注入6例严重血友病B患者的外周静脉(FIX活性为正常值的1%)。研究参与者按顺序进入三个队列中的一个(给予高、中、低剂量的载体)，每组两名参与者。在没有免疫抑制治疗的情况下给予载体，并对参与者进行了6至16个月的跟踪调查。在所有参与者中观察到AAV介导的FIX表达水平为正常水平的2%至11%。在6个停止的FIX预防中，有4个没有自发性出血；在另外两个中，预防性注射的间隔增加。在接受高剂量载体注射的两名参与者中，一人的血清转氨酶水平出现一过性的无症状升高，这与在外周血中检测到AAV8衣壳特异性T细胞有关；另一人的肝酶水平略有上升，原因尚不清楚。这两名参与者每人都接受了短期的糖皮质激素治疗，迅速使转氨酶水平正常化，并将固定水平维持在正常值的3%至11%的范围内。外周静脉注射scAAV2/8-LP1-hFIXco后，FIX转基因表达水平足以改善出血表型，且副作用很少。虽然免疫介导的AAV转导的肝细胞清除仍是一个令人担忧的问题，但这一过程可以通过短疗程的糖皮质激素控制，而不会丢失转基因表达。(由医学研究理事会和其他机构资助；ClinicalTrials.gov编号，NCT00979238。)
Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. We investigated the use of a new gene therapy in patients with the disorder. We infused a single dose of a serotype-8–pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values). Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months. AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid–specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values. Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. (Funded by the Medical Research Council and others; ClinicalTrials.gov number, NCT00979238.)