Treating Cystic Fibrosis with mRNA and CRISPR

Abstract

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.

Inhalable polymer nanoparticles for versatile mRNA delivery and mucosal vaccination

“…Ease of epithelial cell targeting is a primary advantage of inhaled delivery strategies (27). Protein replacement therapy via mRNA delivery to epithelial cells is therapeutically relevant for a host of diseases such as cystic fibrosis (CF) (42), asthma (43), surfactant B protein deficiency (44), and alpha-1-antitrypsin deficiency (45). Our epithelial transfection rate of >20% after a single dose suggests that protein expression will be therapeutically relevant; prior research has shown that for significant disease mitigation only a fraction of lung cells in CF need to express CFTR.…”

Drug delivery systems for RNA therapeutics

“…1b ). mRNA can be used to replace protein, using replacement therapies 57 ; to reduce protein levels, using Cas9 cutting approaches 58 ; or to repair protein mutations at the DNA level, using base editing 59 , 60 . In 2021, researchers reported the successful use of LNPs encapsulating Streptococcus pyogenes Cas9 (CRISPR-associated endonuclease Cas9) mRNA and a CRISPR guide RNA in six patients with hATTR amyloidosis with polyneuropathy; a single 0.3 mg/kg dose resulted in a mean reduction from baseline of blood transthyretin (TTR) levels of 87% at 28 days post-dose 58 .…”

Current Advances in RNA Therapeutics for Human Diseases

“…mRNAs are excellent candidates for the treatment of diseases with a known genetic component. Traditionally, mRNAs have been used for replacement therapy when diseases are caused by a lack of expression of a particular protein [ 70 ]. Additionally, CRISPR–Cas-based mRNA therapies can be used to repair DNA mutations that cause non-functional downstream products [ 71 ].…”