Pérez-Iturralde Andrea, Carte Beatriz, Aldabe Rafael
Gene Therapy Area, Foundation for Applied Medical Research, University of Navarra, IdisNA, Pamplona, Spain.
Hum Gene Ther. 2021 Oct;32(19-20):1242-1250. doi: 10.1089/hum.2021.171.
The efficiency of recombinant adeno-associated virus (AAV) vectors transducing host cells is very low, limiting their therapeutic potential in patients. There are several cellular pathways interacting and interfering with the journey of the AAV from the cell surface to the nucleus, opening the possibility to enhance AAV transduction by modifying these interactions. In this study, we explored the results of AAV hepatic transduction when different mammalian target of rapamycin (mTOR) inhibitors, rapamycin, MLN0128, RapaLink-1, were used in preconditioned juvenile and adult mice. We confirmed rapamycin as an AAV hepatic transduction enhancer in juvenile and adult mice; however, RapaLink-1, a stronger mTOR inhibitor and a clear hepatic autophagy inducer, had no positive effect. Moreover, MLN0128 reduced AAV hepatic transduction. Therefore, our results show a complex interaction between the mTOR pathway and AAV-mediated hepatic transduction and indicate that mTOR inhibition is not a straightforward strategy for improving AAV transduction. More studies are necessary to elucidate the molecular mechanisms involved in the positive and negative effects of mTOR inhibitors on AAV transduction efficiency.
重组腺相关病毒（AAV）载体转导宿主细胞的效率非常低，限制了它们在患者中的治疗潜力。有几种细胞途径会相互作用并干扰AAV从细胞表面到细胞核的进程，这为通过修饰这些相互作用来提高AAV转导效率提供了可能性。在本研究中，我们探究了在预处理的幼年和成年小鼠中使用不同的哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂（雷帕霉素、MLN0128、RapaLink-1）时AAV肝脏转导的结果。我们证实雷帕霉素是幼年和成年小鼠中AAV肝脏转导的增强剂；然而，更强的mTOR抑制剂且是明确的肝脏自噬诱导剂RapaLink-1却没有积极作用。此外，MLN0128降低了AAV肝脏转导。因此，我们的结果显示了mTOR途径与AAV介导的肝脏转导之间存在复杂的相互作用，并表明抑制mTOR并非提高AAV转导的直接策略。需要更多研究来阐明mTOR抑制剂对AAV转导效率产生正负效应所涉及的分子机制。
