Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy
Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy
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DOI：
10.1182/blood-2008-10-181479
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发表时间：
2009-01-22
期刊：
影响因子：
20.3
通讯作者：
Lothrop, Clinton D., Jr.
中科院分区：
文献类型：
--
作者：
Niemeyer, Glenn P.;Herzog, Roland W.;Lothrop, Clinton D., Jr.
临床前研究和初步临床试验已经证明了腺相关病毒（AAV）介导的血友病B基因治疗的可行性。在一项为期8年的研究中，接受肝脏定向AAV 2因子IX（FIX）基因治疗的易出血性血友病B犬（n = 2）未发生需要FIX置换的单次出血，而接受肌肉定向基因治疗的犬（n = 3）的出血频率与未接受治疗的FIX缺陷犬相似。在接受肝脏定向基因治疗的2只犬中，凝血试验（全血凝血时间[WBCT]、活化凝血时间[ACT]和活化部分凝血活酶时间[aPTT]）保持在正常范围的上限。FIX活性在两种肝脏处理犬中均保持稳定在4%至10%之间，但在接受肌肉定向基因转移的犬中检测不到。通过线性扩增介导的聚合酶链反应（LAM-PCR）的整合位点分析表明，载体序列主要以染色体外形式存在。全血细胞计数（CBC）、血清化学、胆汁酸谱、肝脏磁共振成像（MRI）和计算机断层扫描（CT）扫描以及肝脏活检均正常，无肿瘤形成证据。AAV介导的肝脏定向基因治疗纠正了血友病表型，而没有毒性或抑制剂的发展，在走廊倾向的无效突变狗超过8年。（血。2009;113：797-806）
Preclinical studies and initial clinical trials have documented the feasibility of adenoassociated virus (AAV)-mediated gene therapy for hemophilia B. In an 8-year study, inhibitor-prone hemophilia B dogs (n = 2) treated with liver-directed AAV2 factor IX (FIX) gene therapy did not have a single bleed requiring FIX replacement, whereas dogs undergoing muscle-directed gene therapy (n = 3) had a bleed frequency similar to untreated FIX-deficient dogs. Coagulation tests (whole blood clotting time [WBCT], activated clotting time [ACT], and activated partial thromboplastin time [aPTT]) have remained at the upper limits of the normal ranges in the 2 dogs that received liver-directed gene therapy. The FIX activity has remained stable between 4% and 10% in both liver-treated dogs, but is undetectable in the dogs undergoing muscle-directed gene transfer. Integration site analysis by linear amplification-mediated polymerase chain reaction (LAM-PCR) suggested the vector sequences have persisted predominantly in extrachromosomal form. Complete blood count (CBC), serum chemistries, bile acid profile, hepatic magnetic resonance imaging (MRI) and computed tomography (CT) scans, and liver biopsy were normal with no evidence for tumor formation. AAV-mediated liver-directed gene therapy corrected the hemophilia phenotype without toxicity or inhibitor development in the inhibitor-prone null mutation dogs for more than 8 years. (Blood. 2009;113: 797-806)