Therapeutic levels of human factor VIII and IX using HIV-1-based lentiviral vectors in mouse liver
Therapeutic levels of human factor VIII and IX using HIV-1-based lentiviral vectors in mouse liver
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DOI：
10.1182/blood.v96.3.1173.015k34_1173_1176
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发表时间：
2000-08-01
期刊：
影响因子：
20.3
通讯作者：
Kay, MA
中科院分区：
文献类型：
--
作者：
Park, F;Ohashi, K;Kay, MA
慢病毒载体有可能在血友病基因治疗中发挥重要作用。本研究使用了基于人类免疫缺陷病毒(HIV)的慢病毒载体，该慢病毒载体含有EF1α增强子/启动子，可驱动人第VIII因子(HFVIII)或第IX因子(HFIX)的互补DNA表达，用于门静脉注射C57B1/6小鼠。随着表达hFIX慢病毒剂量的增加，血清hFIX水平呈剂量依赖性持续升高，高达50-60 ng/ml；肝部分切除组血清hFIX水平高达350 ng/ml，是未切除组的4-6倍(P<；0.005)。免疫缺陷C57BI/6SCID小鼠血浆中hFVIII的表达达到30 ng/mL(正常水平的15%)，但随着抗hFVIII抗体的产生而下降，hFVIII的表达是短暂的，但在免疫缺陷的C57BI/6 SCID小鼠中，hFVIII的表达持续存在，提示免疫活性小鼠的体液免疫受限基因表达。本研究证明慢病毒载体可以在体内产生治疗性水平的凝血因子，这种水平可以随着肝细胞的增殖而增强。(C)2000年，由美国血液病学会提供。
Lentiviral Vectors have the potential to play an important role In hemophilia gene therapy. The present study used human immunodeficiency virus (HIV)-based lentiviral vectors containing an EF1 alpha enhancer/promoter driving human factors VIII (hFVIII) or IX (hFIX) complementary DNA expression for portal vein injection Into C57B1/6 mice. Increasing doses of hFIX-expressing lentivirus resulted in a dose-dependent, sustained increase in serum hFIX levels up to approximately 50-60 ng/ml, Partial hepatectomy resulted in a 4- to 6-fold increase (P < 0.005) in serum hFIX of up to 350 ng/mL compared with the nonhepatectomized counterparts. The expression of plasma hFVIII reached 30 ng/mL (15% of normal) but was transient as the plasma levels fell concomitant with the formation of anti-hFVIII antibodies, However, hFVIII levels were persistent in immunodeficient C57BI/6 scid mice, suggesting humoral immunity-limited gene expression in immunocompetent mice. This study demonstrates that lentiviral vectors can produce therapeutic levels of coagulation factors in vivo, which can be enhanced with hepatocellular proliferation. (C) 2000 by The American Society of Hematology.