AAV-based CRISPR-Cas9 genome editing: Challenges and engineering opportunities

IF 4.7 3区工程技术 Q2 ENGINEERING, BIOMEDICAL Current Opinion in Biomedical Engineering Pub Date : 2023-12-07 DOI:10.1016/j.cobme.2023.100517

Ami M. Kabadi , Maria Katherine Mejia-Guerra , John D. Graef , Sohrab Z. Khan , Eric M. Walton , Xinzhu Wang , Charles A. Gersbach , Rachael Potter

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Abstract

Recent innovations in the field of gene therapy have paved the way for advances towards developing genome editing medicines. Despite these steps forward, challenges with viral delivery of genome editing tools persist. Efforts currently underway include developing next-generation genome editors, overcoming adeno-associated virus (AAV) packaging restrictions, improving AAV genome integrity, engineering novel AAV capsids, and minimizing the immune response. This review discusses current challenges in delivering CRISPR-Cas nuclease-based genome editing therapies using AAV and highlights emerging methods to overcome these obstacles. This includes developing smaller payloads and regulatory elements, advancing novel sequencing methods for vector characterization, engineering capsids with enhanced potency, tissue-selectivity, and ability to evade pre-existing antibodies, controlling transgene expression, and minimizing the immune response to Cas proteins.

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基于 AAV 的 CRISPR-Cas9 基因组编辑：挑战与工程机遇

基因治疗领域的最新创新为开发基因组编辑药物铺平了道路。尽管取得了这些进展，但基因组编辑工具的病毒传递仍面临挑战。目前正在进行的努力包括开发下一代基因组编辑器、克服腺相关病毒（AAV）包装限制、提高 AAV 基因组完整性、设计新型 AAV 病毒盖以及最大限度地减少免疫反应。本综述讨论了目前使用 AAV 提供基于 CRISPR-Cas 核酸酶的基因组编辑疗法所面临的挑战，并重点介绍了克服这些障碍的新方法。这包括开发更小的有效载荷和调控元件，推进用于载体特征描述的新型测序方法，设计具有更强效力、组织选择性和规避已有抗体能力的噬菌体，控制转基因表达，以及最大限度地减少对 Cas 蛋白的免疫反应。

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