Production, Processing, and Characterization of Synthetic AAV Gene Therapy Vectors,Biotechnology Journal

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Production, Processing, and Characterization of Synthetic AAV Gene Therapy Vectors
Biotechnology Journal ( IF 3.2 ) Pub Date : 2020-09-25 , DOI: 10.1002/biot.202000025
Jihad El Andari _{1,

2} , Dirk Grimm _{1,

2,

3}

Affiliation

Over the last two decades, gene therapy vectors based on wild‐type Adeno‐associated viruses (AAV) are safe and efficacious in numerous clinical trials and are translated into three approved gene therapy products. Concomitantly, a large body of preclinical work has illustrated the power and potential of engineered synthetic AAV capsids that often excel in terms of an organ or cell specificity, the efficiency of in vitro or in vivo gene transfer, and/or reactivity with anti‐AAV immune responses. In turn, this has created a demand for new, scalable, easy‐to‐implement, and plug‐and‐play platform processes that are compatible with the rapidly increasing range of AAV capsid variants. Here, the focus is on recent advances in methodologies for downstream processing and characterization of natural or synthetic AAV vectors, comprising different chromatography techniques and thermostability measurements. To illustrate the breadth of this portfolio, two chimeric capsids are used as representative examples that are derived through forward‐ or backwards‐directed molecular evolution, namely, AAV‐DJ and Anc80. Collectively, this ever‐expanding arsenal of technologies promises to facilitate the development of the next AAV vector generation derived from synthetic capsids and to accelerate their manufacturing, and to thus boost the field of human gene therapy.

中文翻译：

合成AAV基因治疗载体的生产，加工和表征

在过去的二十年中，基于野生型腺相关病毒（AAV）的基因治疗载体在众多临床试验中都是安全有效的，并已转化为三种获批的基因治疗产品。随之而来的是，大量的临床前研究表明，工程合成的AAV衣壳的功能和潜力通常在器官或细胞特异性，体外或体内基因转移的效率和/或与抗AAV的反应性方面表现出色免疫反应。反过来，这就产生了对新的，可扩展的，易于实现的，即插即用的平台过程的需求，这些过程与迅速增加的AAV衣壳变体范围兼容。在这里，重点是对天然或合成AAV载体的下游处理和表征方法的最新进展，包括不同的色谱技术和热稳定性测量。为了说明这种投资组合的广度，使用两个嵌合衣壳作为代表性实例，它们是通过前向或后向分子进化而衍生的，即AAV-DJ和Anc80。总的来说，这个不断扩展的技术库有望促进合成衣壳衍生的下一代AAV载体的开发，并加速其生产，从而扩大人类基因治疗领域。

更新日期：2020-09-25

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