Gene Therapeutics for Surfactant Dysfunction Disorders: Targeting the Alveolar Type 2 Epithelial Cell

Genetic disorders of surfactant dysfunction result in significant morbidity and mortality, among infants, children, and adults. Available medical interventions are limited, nonspecific, 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 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 gene-based therapeutics designed to target and transduce the AT2 cells.

Automated summary

Genetic disorders causing dysfunction in pulmonary surfactant production and function have significant impacts on the morbidity and mortality of infants, children, and adults. Current medical interventions are limited in effectiveness. Gene-based therapeutics show promise as a definitive therapy for these disorders. This review focuses on the pathophysiology and gene-based therapeutic strategies targeting alveolar type 2 cells.