Mucus degrading enzymes for pulmonary drug delivery and therapy

Inhaled drug delivery for the treatment of respiratory diseases has the advantage of directly delivering the therapeutic to the site of disease. This is particularly attractive for many biologics (e.g. DNA- or protein-based) as it bypasses the harsh conditions of gastrointestinal (GI) delivery and the first-pass effect.

However, the viscoelastic mucus layer, which has developed to trap and excrete foreign objects, presents a barrier to delivery. A major component of this barrier are the heavily O-glycosylated mucin proteins.

Overproduced mucus in key diseases for inhalation therapies such as asthma and cystic fibrosis exacerbates this problem.

This project aims to develop specific enzymes to degrade the mucins and thereby attenuate this delivery barrier for biologics. A specialised class of mucin-degrading enzymes are mucinases. These are produced by bacteria and are frequently found in the GI tract of healthy humans.

Such mucinase candidates will be engineered by directed evolution to efficiently and specifically cleave the mucins of the lung environment. However, there currently exist no methods to screen mucin degradation in the large number of mutants required.

Therefore, this project will start by developing two methods for the high-throughput directed evolution of mucinases, leveraging particle-based and microfluidic approaches to screen for mucin degradation. The potential of the developed mucinases to enhance drug delivery will then be evaluated in vitro.