Improving cystic fibrosis (CF) therapies for people who do not respond to existing remedial therapies is of paramount importance. 
DNases are enzymes that reduce the viscosity of bronchial mucus, but are not very resistant inside the bronchi because they are degraded by the action of a particular protein, actin. However, it has been seen that if DNases undergo a chemical modification, called PEGylation, their therapeutic efficacy improves and there is a reduction in mucus viscosity with improved lung function. 

The researchers used variants of DNase1 chemically modified by PEGylation and evaluated their in vitro activity on artificial mucus and samples from persons with CF, with and without actin. The aerodynamic properties of PEGylated DNase1 were examined and computational techniques were used to reconstruct and express improved variants.
In addition, two model organisms, Pichia pastoris (yeast) and Escherichia coli (bacterium), were used to improve the production of the enzyme DNase1L2, which belongs to the same family as DNase1 but is longer-acting, resistant to inhibition by actin and active at acid pH.
Finally, the effectiveness of the variants was analysed on mucus samples.

Overall, the researchers obtained a PEGylated variant of DNase1 (called PEG24mer) with better actin resistance and improved mucus viscosity reduction. They also obtained active DNase1L2, albeit in low yield, and other DNase variants with excellent properties, showing the therapeutic potential of the new DNase versions.

The next step will be to improve the expression of DNase1L2 and optimise the PEGylated variants to increase their efficacy. Further preclinical studies will be necessary to assess the therapeutic potential of these variants in cystic fibrosis therapies.