Pulmonary surfactant is critically important to prevent
atelectasis by lowering the surface tension of the alveolar lining liquid. While
respiratory distress syndrome (RDS) is common in premature infants, severe RDS in term and late preterm infants suggests an underlying genetic etiology. Pathogenic variants in the genes encoding key components of
pulmonary surfactant including
surfactant protein B (SP-B, SFTPB gene),
surfactant protein C (SP-C, SFTPC gene), and the
ATP-Binding Cassette transporter A3 (ABCA3, ABCA3 gene) result in severe neonatal RDS or childhood
interstitial lung disease (chILD). These
proteins play essential roles in
pulmonary surfactant biogenesis and are expressed in alveolar epithelial type II cells (AEC2), the progenitor cell of the alveolar epithelium. SP-B deficiency most commonly presents in the neonatal period with severe RDS and requires
lung transplantation for survival. SFTPC mutations act in an autosomal dominant fashion and more commonly presents with chILD or
idiopathic pulmonary fibrosis than neonatal RDS. ABCA3 deficiency often presents as neonatal RDS or chILD. Gene therapy is a promising option to treat monogenic
lung diseases. Successes and challenges in developing gene
therapies for
genetic disorders of
surfactant dysfunction include viral vector design and tropism for target cell types. In this review, we explore adeno-associated virus (AAV), lentiviral, and adenoviral (Ad)-based vectors as delivery vehicles. Both gene addition and gene editing strategies are compared to best design treatments for
lung diseases resulting from pathogenic variants in the SFTPB, SFTPC, and ABCA3 genes.