University of Eastern Finland, A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, P.O. Box 1627, FIN-70211, Kuopio, Finland.
University of Aarhus, Department of Biomedicine, Ole Worms Allé 3, DK-8000, Aarhus C, Denmark.
Sci Rep. 2017 Mar 24;7(1):386. doi: 10.1038/s41598-017-00376-5.
Adenoviruses are very efficient vectors for delivering therapeutic genes in preclinical and clinical trials. However, randomized controlled human trials have often been lacking clear clinically relevant results. We hypothesized that high lipid levels and specific lipoproteins could significantly decrease adenoviral transduction efficiency in vivo. Here we demonstrate that mice on a high fat diet have lower transgene expression compared to mice on a regular chow. In addition, on a high fat diet, ApoE mice have much higher plasma transgene levels compared to LDLR-deficient mice. We also found that specific lipoprotein receptors play an important role in adenoviral transduction. These findings suggest that high plasma lipid levels, especially apoE-containing lipoproteins, reduce efficacy of adenoviral transduction in mice, which implies that high cholesterol levels in humans could be protective against viral infections and also lead to insufficient transgene expression in clinical trials using adenoviral vectors.
腺病毒在临床前和临床试验中是非常有效的治疗基因传递载体。然而，随机对照的人体试验往往缺乏明确的临床相关结果。我们假设高脂质水平和特定脂蛋白会显著降低体内腺病毒转导效率。在这里，我们证明高脂肪饮食的小鼠与正常饮食的小鼠相比，转基因表达水平较低。此外，在高脂肪饮食的情况下，ApoE 小鼠的血浆转基因水平比 LDLR 缺陷型小鼠高得多。我们还发现特定的脂蛋白受体在腺病毒转导中发挥重要作用。这些发现表明，高血浆脂质水平，特别是含有 apoE 的脂蛋白，会降低小鼠中腺病毒转导的效果，这意味着人类的高胆固醇水平可能对病毒感染具有保护作用，同时也会导致使用腺病毒载体的临床试验中转基因表达不足。
