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Treating Cystic Fibrosis: To Splice or Not to Splice?

Cystic Fibrosis

Cystic Fibrosis (CF) is an autosomal recessive genetic disorder, caused by the dysfunction of the CF transmembrane conductance regulator (CFTR). A variety of causative mutations have been identified, which result in differing levels of disease severity. These mutations have been proven to impact nearly every molecular mechanism required for CFTR function.

To counter these malfunctions, a plethora of small molecular therapeutics known as CFTR modulators have been developed. They function via a range of mechanisms. For example, through stabilising the protein, correcting folding or trafficking defects or rescuing ion transport malfunctions.

A recent study, published in Cell, has added a new and exciting modulator to this long list. CaNDY is a small molecule which acts by correcting an mRNA splicing defect, rescuing the expression of a functional CFTR.

Splicing Modulators

The authors aimed to target a common mutation which causes the inappropriate insertion of a “pseudo exon” into the CFTR mRNA sequence. As a result, the open reading frame is disrupted and the CFTR protein is incorrectly translated. Therefore, the researchers explored specific therapies which could remove this exon, to enhance the expression of functional CFTR.

These pseudo exons are produced by the activity of an exonic splicing enhancer (ESE), combined with serine/arginine-rich splicing factors (SRSFs). However, these splicing factors require a phosphorylation reaction in order to function, therefore the researchers targeted kinases known to activate SRSFs. They screened 747 different kinase inhibitors and identified a small molecule of interest, called CaNDY. CaNDY was shown to rescue the expression of CFTR, as well as its trafficking and channel activity. Although CaNDY will need further clinical validation using organoids and human trials, these results are highly promising.

This study highlights the importance or RNA splicing as a therapeutic target. It also demonstrates that a deep mechanistic understanding of disease processes can lead to effective personalised therapies. In the future, CaNDY and other kinase inhibitors could prove useful for a range of disorders caused by the activation of pseudo exons.

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Cystic Fibrosis / mRNA