Mathiesen Sophie N, Lock Jasmine L, Schoderboeck Lucia, Abraham Wickliffe C, Hughes Stephanie M
Department of Biochemistry, Brain Health Research Centre, Brain Research New Zealand-Rangahau Roro Aotearoa, University of Otago, Dunedin 9016, New Zealand.
Department of Psychology, Brain Health Research Centre, Brain Research New Zealand-Rangahau Roro Aotearoa, University of Otago, Dunedin 9016, New Zealand.
Mol Ther Methods Clin Dev. 2020 Oct 20;19:447-458. doi: 10.1016/j.omtm.2020.10.011. eCollection 2020 Dec 11.
Adeno-associated viral (AAV) vectors are attractive tools for central nervous system (CNS) gene therapy because some vectors can cross the blood-brain barrier (BBB), allowing them to be used as minimally invasive treatments. A novel AAV vector recently evolved , AAV-PHP.eB, has been reported to cross the BBB more effectively than the existing gold standard AAV9, but not under all conditions. Here, we compared the efficacy of single-stranded AAV-PHP.eB and AAV9 in targeting mouse CNS and peripheral tissues after administration via various routes, in two different mouse strains (C57BL/6J and B6C3), and after packaging AAV-PHP.eB with a self-complementary genome. We found that AAV-PHP.eB produced higher CNS transduction than AAV9 after intravenous injection, but only in C57BL/6J and not in B6C3 mice. AAV-PHP.eB and AAV9 produced similar CNS transduction when the administration route did not require the vectors to cross the BBB. Packaging AAV-PHP.eB with a self-complementary genome increased overall CNS transduction, but at the expense of strong neuronal tropism. AAV-PHP.eB resulted in less transduction of liver tissue than AAV9 under all conditions. Taken together, these results suggest the potential for AAV-PHP.eB as a vector for CNS gene therapy applications, but consideration will be required for translation beyond mouse models.
腺相关病毒（AAV）载体是中枢神经系统（CNS）基因治疗的有吸引力的工具，因为一些载体可以穿过血脑屏障（BBB），使其能够用作微创治疗。最近进化出一种新型AAV载体，即AAV-PHP.eB，据报道它比现有的金标准AAV9更有效地穿过血脑屏障，但并非在所有条件下都如此。在这里，我们比较了单链AAV-PHP.eB和AAV9在通过各种途径给药后，在两种不同小鼠品系（C57BL/6J和B6C3）中以及用自我互补基因组包装AAV-PHP.eB后，靶向小鼠中枢神经系统和外周组织的效果。我们发现，静脉注射后，AAV-PHP.eB在中枢神经系统中的转导效率高于AAV9，但仅在C57BL/6J小鼠中如此，在B6C3小鼠中则不然。当给药途径不需要载体穿过血脑屏障时，AAV-PHP.eB和AAV9产生相似的中枢神经系统转导。用自我互补基因组包装AAV-PHP.eB可提高整体中枢神经系统转导效率，但以牺牲强大的神经元嗜性为代价。在所有条件下，AAV-PHP.eB导致的肝组织转导比AAV9少。综上所述，这些结果表明AAV-PHP.eB作为中枢神经系统基因治疗应用载体的潜力，但在从小鼠模型转化应用时需要考虑更多因素。
