Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.
Department of Medical and Molecular Sciences, University of Delaware, Newark, DE 19716, USA.
Int J Mol Sci. 2020 May 13;21(10):3433. doi: 10.3390/ijms21103433.
The humoral immune response elicited by adeno-associated virus (AAV)-mediated gene therapy for the treatment of mucopolysaccharidoses (MPS) poses a significant challenge to achieving therapeutic levels of transgene expression. Antibodies targeting the AAV capsid as well as the transgene product diminish the production of glycosaminoglycan (GAG)-degrading enzymes essential for the treatment of MPS. Patients who have antibodies against AAV capsid increase in number with age, serotype, and racial background and are excluded from the clinical trials at present. In addition, patients who have undergone AAV gene therapy are often excluded from the additional AAV gene therapy with the same serotype, since their acquired immune response (antibody) against AAV will limit further efficacy of treatment. Several methods are being developed to overcome this immune response, such as novel serotype design, antibody reduction by plasmapheresis and immunosuppression, and antibody evasion using empty capsids and enveloped AAV vectors. In this review, we examine the mechanisms of the anti-AAV humoral immune response and evaluate the strengths and weaknesses of current evasion strategies in order to provide an evidence-based recommendation on evading the immune response for future AAV-mediated gene therapies for MPS.
腺相关病毒（AAV）介导的基因治疗治疗黏多糖贮积症（MPS）所引起的体液免疫反应对实现转基因表达的治疗水平构成了重大挑战。针对 AAV 衣壳和转基因产物的抗体减少了治疗 MPS 所必需的糖胺聚糖（GAG）降解酶的产生。目前，针对 AAV 衣壳的抗体的患者数量随着年龄、血清型和种族背景的增加而增加，并被排除在临床试验之外。此外，接受过 AAV 基因治疗的患者通常被排除在相同血清型的额外 AAV 基因治疗之外，因为他们对 AAV 的获得性免疫反应（抗体）将限制治疗的进一步疗效。目前正在开发几种方法来克服这种免疫反应，例如新型血清型设计、通过血浆置换和免疫抑制减少抗体，以及使用空衣壳和包膜 AAV 载体逃避抗体。在这篇综述中，我们研究了抗 AAV 体液免疫反应的机制，并评估了当前逃避策略的优缺点，以便为未来用于治疗 MPS 的 AAV 介导的基因治疗提供逃避免疫反应的循证建议。
