LAUSR

Genetic disorders of surfactant dysfunction result in significant morbidity and mortality, among infants, children, and adults. Available medical interventions are limited, non-specific and generally ineffective. As such, the need for effective therapies remains. Pathogenic variants in the SFTPB, SFTPC, and ABCA3 genes, each of which encode proteins essential for proper pulmonary surfactant production and function, result in interstitial lung disease in infants, children, and adults, and lead to morbidity and early mortality. Expression of these genes is predominantly limited to the alveolar type 2 (AT2) epithelial cells that are present in the distal airspaces of the lungs, thus providing an unequivocal cellular origin of disease pathogenesis. While several treatment strategies are under development, a gene-based therapeutic holds great promise as a definitive therapy. Importantly for clinical translation, the genes associated with surfactant dysfunction are both well-characterized and amenable to a gene-therapeutic-based strategy. This review focuses on the pathophysiology associated with these genetic disorders of surfactant dysfunction and also provides an overview of the current state of the gene-based therapeutics designed to target and transduce the AT2 cells.