Gene Therapy Potential for Genetic Disorders of Surfactant Dysfunction

Abstract

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.

Keywords: AEC2; AT2; ATII; alveoli; pulmonary disease; surfactant deficiency; viral vectors.

FIGURE 1

Schematic of SP-B, SP-C, and ABCA3 protein localization in an alveolar type II cell. 1) ABCA3 transports phospholipids into lamellar bodies; SP-B and SP-C provide support during surfactant assembly. 2) Lamellar bodies undergo exocytosis from alveolar type II cell and unravel into tubular myelin. 3) Tubular myelin disassembles into a surfactant monolayer through adsorption into a film at an air-liquid interface.

FIGURE 2

(A) Top panel: Exon representation of SFTPB on chromosome 2. Middle panels: progression of protein processing. Glycosylation at residues 129-131 and 311-313 occurs in ER. Bottom panel: yellow circles indicate oligomer of at least 6 homo-dimers inserted into a lipid bilayer. (B) Top panel: Exon representation of SFTPC on chromosome 8. Middle panels: progression of protein processing. Palmitoylation occurs in the Golgi apparatus. Cleavage events resulting in shortened protein forms are the result of Cathepsin H and Pepsinogen C enzymatic activities. Bottom panel: yellow circles indicate mature membrane bound protein. (C) Top panel: Exon representation of ABCA3 on chromosome 16. Middle panel: N-linked glycosylation at positions N124 and N140 indicated by N-linked glycosylation symbol. Bottom panel: N-terminus is proteolytically cleaved by cathepsins L and B, as indicated by scissors icon in EL1. TM, transmembrane domain; EL, extracellular loop; NBD, nucleotide binding domain; aa, amino acid.