Therapeutic oligonucleotides are a novel chemical modality with unique characteristics that offer significant therapeutic potential. With the latest surge in development, they are paving the way to the market at a rapid pace. To support that, scalable and economically sustainable oligonucleotide production is required. The upstream part exploits the well-studied phosphoramidite chemistry, known from the 1960s, using automated synthesis on a solid support. On the other hand, the downstream processing, which consists of purification and isolation steps, has stayed in the shadow of the more thoroughly studied synthesis, even though it is often regarded as the bottleneck of therapeutic oligonucleotide production. Therefore, this review aims to highlight the most important traditional purification and isolation approaches for the production of therapeutic oligonucleotides that ensure product quality, yields, scale, and cost-efficiency as well as newly emerging separation technologies that could become relevant in the future.

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治疗性寡核苷酸纯化和分离的概述和最新进展


治疗性寡核苷酸是一种新型化学形式，具有独特的特性，具有重要的治疗潜力。随着最新的发展浪潮，他们正在快速进入市场。为了支持这一点，需要规模化且经济可持续的寡核苷酸生产。上游部分利用了 1960 年代已知的经过充分研究的亚磷酰胺化学，在固体载体上使用自动合成。另一方面，下游工艺（包括纯化和分离步骤）一直处于研究更深入的合成的阴影下，尽管它通常被视为治疗性寡核苷酸生产的瓶颈。因此，本综述旨在重点介绍用于生产治疗性寡核苷酸的最重要的传统纯化和分离方法，以确保产品质量、产量、规模和成本效益，以及未来可能成为现实的新兴分离技术。