Gene transfer with high doses of adeno-associated viral (AAV) vectors has resulted in serious adverse events and even death of the recipients. Toxicity could most likely be circumvented by repeated injections of lower and less toxic doses of vectors. This has not been pursued as AAV vectors induce potent neutralizing antibodies, which prevent cell transduction upon reinjection of the same vector. This review discusses different types of immune responses against AAV vectors and how they offer targets for the elimination or inhibition of vector-specific neutralizing antibodies. Such antibodies can be circumvented by using different virus serotypes for sequential injections, they can be removed by plasmapheresis, or they can be destroyed by enzymatic degradation. Antibody producing cells can be eliminated by proteasome inhibitors. Drugs that inhibit T-cell responses, B-cell signaling, or presentation of the vector’s antigens to B cells can prevent or reduce induction of AAV-specific antibodies. Combinations of different approaches and drugs are likely needed to suppress or eliminate neutralizing antibodies, which would then allow for repeated dosing. Alternatively, novel AAV vectors with higher transduction efficacy are being developed and may allow for a dose reduction, although it remains unknown if this will completely address the problem of high-dose adverse events.

使用高剂量腺相关病毒 (AAV) 载体进行基因转移会导致严重的不良事件，甚至导致接受者死亡。毒性很可能通过重复注射较低和较低毒性剂量的载体来规避。这还没有被追求，因为 AAV 载体会诱导有效的中和抗体，从而防止在重新注射同一载体时发生细胞转导。这篇综述讨论了针对 AAV 载体的不同类型的免疫反应，以及它们如何为消除或抑制载体特异性中和抗体提供目标。此类抗体可以通过使用不同的病毒血清型进行连续注射来规避，它们可以通过血浆去除术去除，或者它们可以通过酶促降解被破坏。产生抗体的细胞可以被蛋白酶体抑制剂消除。抑制 T 细胞反应、B 细胞信号传导或将载体抗原呈递给 B 细胞的药物可以防止或减少 AAV 特异性抗体的诱导。可能需要不同方法和药物的组合来抑制或消除中和抗体，然后允许重复给药。或者，正在开发具有更高转导效率的新型 AAV 载体，并可能允许减少剂量，尽管尚不清楚这是否会完全解决高剂量不良事件的问题。