Treating cystic fibrosis with mRNA and CRISPR.
Hum Gene Ther. 2020 Aug 16;:
Authors: Sanchez ADS, Paunovska K, Cristian A, Dahlman J
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 ASO-based drugs have revealed three key concepts that will likely extend to mRNA therapies delivered by non-viral 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. Here, 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 non-viral mRNA or CRISPR-based drugs to treat CF successfully in patients.
PMID: 32799680 [PubMed – as supplied by publisher]