Less than 20% of the protein coding genome is thought to be targetable using small molecules. mRNA therapies are not limited in the same way since in theory, they can silence or edit any gene by encoding CRISPR nucleases, or alternatively, produce any missing protein. Yet not all mRNA therapies are equally likely to succeed. Over the past several years, an increasing number of clinical trials with siRNA- and antisense oligonucleotide-based drugs have revealed three key concepts that will likely extend to mRNA therapies delivered by nonviral systems. First, scientists have come to understand that some genes make better targets for RNA therapies than others. Second, scientists have learned that the type and position of chemical modifications made to an RNA drug can alter its therapeutic window, toxicity, and bioavailability. Third, scientists have found that safe and targeted drug delivery vehicles are required to ferry mRNA therapies into diseased cells. In this study, we apply these learnings to cystic fibrosis (CF). We also describe lessons learned from a subset of CF gene therapies that have already been tested in patients. Finally, we highlight the scientific advances that are still required for nonviral mRNA- or CRISPR-based drugs to treat CF successfully in patients.

中文翻译：

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用 mRNA 和 CRISPR 治疗囊性纤维化。


不到 20% 的蛋白质编码基因组被认为可以使用小分子进行靶向。 mRNA 疗法并不以同样的方式受到限制，因为从理论上讲，它们可以通过编码 CRISPR 核酸酶来沉默或编辑任何基因，或者产生任何缺失的蛋白质。然而，并非所有 mRNA 疗法都有相同的成功机会。在过去的几年中，越来越多的基于 siRNA 和反义寡核苷酸的药物的临床试验揭示了三个关键概念，这些概念可能会扩展到非病毒系统提供的 mRNA 疗法。首先，科学家们已经认识到，某些基因比其他基因更适合 RNA 疗法。其次，科学家们了解到，RNA 药物化学修饰的类型和位置可以改变其治疗窗口、毒性和生物利用度。第三，科学家们发现需要安全且有针对性的药物递送载体来将 mRNA 疗法运送到患病细胞中。在这项研究中，我们将这些知识应用于囊性纤维化（CF）。我们还描述了从已经在患者身上进行测试的 CF 基因疗法子集中吸取的经验教训。最后，我们强调非病毒 mRNA 或 CRISPR 药物要成功治疗 CF 患者仍需要科学进步。