Treating Cystic Fibrosis with mRNA and CRISPR

Hum Gene Ther. 2020 Sep;31(17-18):940-955. doi: 10.1089/hum.2020.137. Epub 2020 Sep 8.


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.

Keywords: CRISPR; LNP; barcoding; cystic fibrosis; mRNA; nanoparticle.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • CRISPR-Cas Systems*
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / therapy*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Gene Editing / methods*
  • Genetic Therapy / methods*
  • Humans
  • RNA, Messenger / administration & dosage*
  • RNA, Messenger / genetics


  • CFTR protein, human
  • RNA, Messenger
  • Cystic Fibrosis Transmembrane Conductance Regulator