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基因治疗对乙型血友病有效

2011/12/13 来源:生物谷
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英国伦敦大学学院的Amit Nathwani博士等研究发现,基因治疗对乙型血友病有效。其研究结果近日发表在《新英格兰医学》(New England Journal of Medicine)上。

基因治疗对乙型血友病有效

英国伦敦大学学院的Amit Nathwani博士等研究发现,基因治疗对乙型血友病有效。其研究结果近日发表在《新英格兰医学》(New England Journal of Medicine)上。

人类在很久前就发现了血友病,但首次发现IX因子(FIX)缺乏可导致血友病是在1952年,患者为一位名叫Stephen Christmas 的10岁男孩,因此该病被命名为Christmas病。

之前有报道使用腺相关病毒(AAV)载体对该病进行基因治疗,但因T细胞免疫反应导致仅有一过性表达FIX。

为避免上述情况发生,Nathwani等采用了另外一个修饰后的腺相关病毒血清型8作为载体,该载体在人类研究中较前者少见。其具有嗜肝性,可通过外周静脉进行治疗。

6名患者按照治疗顺序被分为低、中、高剂量组,最早接受治疗者为低剂量组,最晚者为高剂量组,每组2名患者,每组患者的用药量具有梯度性:低剂量组的载体剂量为2×1011 /kg体重,中剂量组为前者的3倍,高剂量组为低剂量组的10倍。

低剂量组的两名患者,其血浆FIX水平为正常的2%,其中一名可停止常规FIX预防,另外一名可增大两次用药间的时间跨度。

中剂量组的FIX水平为正常的3%,其中一名已经停止常规FIX预防,另外一名也已停止并继续板球和橄榄球运动。

高剂量组的一名患者FIX水平达正常的7%,随后其血清转氨酶水平升至正常上限的5倍,在使用强的松治疗后下降,FIX水平下降至正常的3%。在接受了6个月的基因治疗后该患者脱离了常规FIX预防,但因外伤仍需补充血液蛋白质。

最后接受治疗的患者在8周的治疗中,其血清FIX水平达到了正常的8%至12%,并没有使用常规FIX预防,且该患者仍参与马拉松训练。该患者血清转氨酶也有一过性升高,但未达到正常上限。


基因治疗对乙型血友病有效 参考文献

基因治疗对乙型血友病有效 参考文献Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B

Amit C. Nathwani, Edward G.D. Tuddenham, Savita Rangarajan, 

BACKGROUND 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.

METHODS 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.

RESULTS 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.

CONCLUSIONS 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. 

文献链接:http://www.nejm.org/doi/full/10.1056/NEJMoa1108046

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