Development of novel synthetic lung surfactants for treatment of respiratory distress syndrome
Abstract: Pulmonary surfactant is a complex mixture of lipids and specific proteins found in the alveoli and its main role is to reduce the surface tension of the alveolar air/water interface, thereby preventing lung collapse. Lack of pulmonary surfactant in premature babies results in lethal respiratory distress syndrome (RDS), which is today treated with surfactant replacement therapy, i.e. delivery of pulmonary surfactant extracted from animal lungs into the airways. Despite the effectiveness of surfactant replacement therapy, it has several limitations: pronounced batch to batch variability, risk of disease transmission, and expensive source material and production procedures. Moreover, RDS secondary to surfactant inhibition in adults (ARDS) has turned out to be difficult to treat with existing natural derived surfactant preparations, probably for a combination of reasons, such as limited supply and sensitivity to inhibition. The development of synthetic pulmonary surfactants is a tempting solution that could overcome these limitations, but in spite of more than 30 years of development work, there still no synthetic surfactant in clinical use. The two surfactant proteins B (SP-B) and C (SP-C) that are present in natural derived surfactants are difficult to produce or replicate and the lipid composition of natural surfactants is very complex. As a result, the development of simple lipid compositions and surfactant protein analogues that can reproduce the activity of animal derived surfactants is not trivial. In this thesis, we designed surfactant protein analogues and tested their activities in animal models of neonatal RDS and ARDS. We investigated the importance of intramolecular disulfide bonds in an SP-B analogue, and we improved the recombinant production of the SP-C analogue SPC33Leu. Artificial surfactant based on recombinant SP-C33Leu improved lung mechanics in an RDS model and enhanced lung function and reduced inflammation in an ARDS model. Finally, we investigated the novel concept of creating surfactant protein analogues that combine both SP-B and SP-C activities in one polypeptide. We designed and recombinantly produced polypeptides that fuse an SP-B analogue and an SP-C analogue - Combo peptides - and tested mixtures of these analogues with two phospholipid species in an RDS model ventilated without stabilizing end expiration pressures in the lung. Mixtures containing low amounts of Combo peptides improve lung function in a similar manner as a clinically used natural derived surfactant. The Combo peptide approach can deliver simple synthetic surfactants that match currently used natural preparations and can be produced efficiently.
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