In vivo hepatic gene therapy: complete albeit transient correction of factor IX deficiency in hemophilia B dogs.
In vivo hepatic gene therapy: complete albeit transient correction of factor IX deficiency in hemophilia B dogs.
复制标题
体内肝脏基因治疗：彻底但短暂地纠正 B 型血友病犬的 IX 因子缺乏症。
DOI：
10.1073/pnas.91.6.2353
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发表时间：
1994
影响因子：
11.1
通讯作者：
Thompson,AR
中科院分区：
文献类型：
--
作者：
Kay,MA;Landen,CN;Rothenberg,SR;Taylor,LA;Leland,F;Wiehle,S;Fang,B;Bellinger,D;Finegold,M;Thompson,AR
B 型血友病是一种由 IX 因子基因突变引起的出血性疾病。该疾病是 X 连锁隐性遗传疾病，患病率约为 30,000 分之一的白人男性。因子 IX 在肝脏中自然合成并分泌到血液中。在此，我们报道了含有犬因子 IX cDNA 的重组腺病毒载体的构建，该载体能够在体内高效转导小鼠肝细胞，而无需部分肝切除。重组病毒载体通过直接将载体输注到缺陷动物的门脉系统中来治疗B型血友病狗。接受治疗的 B 型血友病狗的血浆因子 IX 浓度从正常狗的水平的 0% 增加到 300%，导致疾病完全改善，如正常的凝血和止血测量结果所示。尽管血浆因子 IX 浓度在几天后开始下降，但治疗动物中因子 IX 的治疗水平持续 1-2 个月。结果验证了体内肝脏基因递送的原理，以重建大型动物模型中的遗传缺陷，并表明当开发出长效载体时，基因治疗是可以实现的。
Hemophilia B is a bleeding disorder caused by mutations in the factor IX gene. The disorder is X-linked recessive with a prevalence of about 1 in 30,000 Caucasian males. Factor IX is naturally synthesized in the liver and secreted into blood. Here we report the construction of recombinant adenoviral vectors containing the canine factor IX cDNA that are capable of transducing hepatocytes in mice at high efficiencies in vivo without partial hepatectomy. The recombinant viral vector was used to treat hemophilia B dogs by direct vector infusion into the portal vasculature of deficient animals. Plasma factor IX concentrations in the treated hemophilia B dogs increased from 0 to 300% of the level present in normal dogs, resulting in complete amelioration of the disease as demonstrated by normal blood coagulation and hemostatic measurements. Although plasma factor IX concentration started to decline after a few days, therapeutic levels of factor IX persisted for 1-2 months in the treated animals. The results validate the principle of in vivo hepatic gene delivery to reconstitute the genetic deficiency in a large animal model and suggest that gene therapy is achievable when long-acting vectors are developed.