Development of a long-acting version of recombinant human deoxyribonuclease I for the treatment of cystic fibrosis lung disease

Recombinant human deoxyribonuclease I (rhDNase) is the mucolytic agent most widely used in cystic fibrosis (CF) treatment. However, its rapid clearance from the lungs implies daily dosing, high therapy burden and reduced patient compliance. In this thesis, we developed a modified rhDNase with sustained residency in the lungs through the PEGylation of the enzyme. Mono-PEGylation of rhDNase with linear 20 kDa, linear 30 kDa or two-arm 40 kDa polyethylene glycol (PEG) preserves its enzymatic activity. It sustains rhDNase presence and mucolytic activity within the lungs for more than 15 days while the unconjugated enzyme is cleared within a day. One dose of PEGylated rhDNase presents a similar efficacy on DNA hydrolysis in the respiratory tract as 5 daily doses of rhDNase. The sustained presence of PEGylated rhDNase in the lungs and its therapeutic efficacy present interesting perspectives for the development of a long-acting rhDNase with a reduced therapy burden.