Dynamics of interferon-specific gene expression in peripheral blood of interferon alfa-naive patients with genotype 1 chronic hepatitis C infection treated with albumin-interferon alfa
Dynamics of interferon-specific gene expression in peripheral blood of interferon alfa-naive patients with genotype 1 chronic hepatitis C infection treated with albumin-interferon alfa
复制标题
DOI：
10.1016/j.hepres.2006.04.005
复制
发表时间：
2006-08-01
影响因子：
4.2
通讯作者：
Subramanian, G. Mani
中科院分区：
文献类型：
--
作者：
Bain, Vincent G.;Yoshida, Eric M.;Subramanian, G. Mani
白蛋白-干扰素α（alb-IFN）是一种新的重组蛋白，其衍生自IFN α-2b基因融合至人白蛋白，其在单个多肽中结合了IFN α的抗病毒特性和白蛋白的长血清半衰期。干扰素α（IFN α）介导的生物学应答源于IFN α与其靶受体的结合以及随后干扰素特异性基因（ISG）表达的调节。ISG表达的动力学在一项2a期研究中进行了评估，该研究在接受alb-IFN治疗的基因型1型慢性丙型肝炎（CHC）的IFN α初治患者中进行。在给药前以及第7天和第28天从47名患者中获得全血，所述患者在200至1200 μ g范围内的5个剂量组中间隔14天接受两次皮下注射alb-IFN。通过TaqMan Real-time PCR测定包括4个ISG的9个候选基因的基因表达。在第7天和第28天，ISG-OAS 1、IRF 7、IFI 44和IF 127存在持续> 5倍的中值诱导。虽然所有受试者均显示出对alb-IFN的分子应答，但观察到治疗前基因表达水平和治疗期间调节倍数的个体差异。在第7天和第28天，OAS 1、IF 144和IRF 7的诱导在个体患者中显示出显著的成对相关性（r > 0.7和P < 0.001）。基线表达或诱导基因表达与抗病毒应答无相关性。总之，alb-IFN表现出对ISG的稳健诱导，这与IFN α相关的分子应答一致。(c)2006爱思唯尔爱尔兰有限公司保留所有战斗。
Albumin-interferon alfa (alb-IFN) is a novel recombinant protein derived from IFN alpha-2b genetically fused to human albumin, which combines in a single polypeptide the antiviral properties of IFN alpha with the long serum half-life of albumin. Interferon alfa (IFN alpha) mediated biological responses stem from the engagement of IFN alpha with its target receptor and subsequent modulation of interferon-specific gene (ISG) expression. The dynamics of ISG expression were evaluated in a Phase 2a study conducted in IFNa naive patients with genotype 1 chronic hepatitis C (CHC) treated with alb-IFN. Whole blood was obtained pre-dose and on days 7 and 28 from 47 patients enrolled to receive two subcutaneous injections of alb-IFN 14 days apart in five dose cohorts ranging from 200 to 1200 mu g. Gene expression of nine candidate genes including four ISGs was determined by a TaqMan Real-time PCR assay. There was sustained > 5-fold median induction on days 7 and 28 of the ISG's-OAS1, IRF7, IFI44 and IF127. While all subjects showed a molecular response to alb-IFN, individual variability in pre-treatment gene expression levels and fold of modulation during treatment was observed. At days 7 and 28, induction of OAS1, IF144 and IRF7 showed significant pair-wise correlation in individual patients (r > 0.7 and P < 0.001). There was no correlation of baseline expression or induction of gene expression with antiviral response. In conclusion, alb-IFN demonstrated robust induction of ISG that was consistent with the molecular response associated with an IFN alpha. (c) 2006 Elsevier Ireland Ltd. All fights reserved.