Gene Therapy Potential for Genetic Disorders of Surfactant Dysfunction
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...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-01-01
|
| Series: | Frontiers in Genome Editing |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fgeed.2021.785829/full |
| _version_ | 1818940481720025088 |
|---|---|
| author | Ashley L. Cooney Ashley L. Cooney Jennifer A. Wambach Patrick L. Sinn Patrick L. Sinn Paul B. McCray Paul B. McCray |
| author_facet | Ashley L. Cooney Ashley L. Cooney Jennifer A. Wambach Patrick L. Sinn Patrick L. Sinn Paul B. McCray Paul B. McCray |
| author_sort | Ashley L. Cooney |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T06:40:20Z |
| format | Article |
| id | doaj.art-fcdff47321004f249cd2be27366c32cb |
| institution | Directory Open Access Journal |
| issn | 2673-3439 |
| language | English |
| last_indexed | 2024-12-20T06:40:20Z |
| publishDate | 2022-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genome Editing |
| spelling | doaj.art-fcdff47321004f249cd2be27366c32cb2022-12-21T19:49:52ZengFrontiers Media S.A.Frontiers in Genome Editing2673-34392022-01-01310.3389/fgeed.2021.785829785829Gene Therapy Potential for Genetic Disorders of Surfactant DysfunctionAshley L. Cooney0Ashley L. Cooney1Jennifer A. Wambach2Patrick L. Sinn3Patrick L. Sinn4Paul B. McCray5Paul B. McCray6Department of Pediatrics, The University of Iowa, Iowa City, IA, United StatesPappajohn Biomedical Institute and the Center for Gene Therapy, The University of Iowa, Iowa City, IA, United StatesEdward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United StatesDepartment of Pediatrics, The University of Iowa, Iowa City, IA, United StatesPappajohn Biomedical Institute and the Center for Gene Therapy, The University of Iowa, Iowa City, IA, United StatesDepartment of Pediatrics, The University of Iowa, Iowa City, IA, United StatesPappajohn Biomedical Institute and the Center for Gene Therapy, The University of Iowa, Iowa City, IA, United StatesPulmonary 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.https://www.frontiersin.org/articles/10.3389/fgeed.2021.785829/fullsurfactant deficiencyviral vectorsalveolipulmonary diseaseAEC2ATII |
| spellingShingle | Ashley L. Cooney Ashley L. Cooney Jennifer A. Wambach Patrick L. Sinn Patrick L. Sinn Paul B. McCray Paul B. McCray Gene Therapy Potential for Genetic Disorders of Surfactant Dysfunction Frontiers in Genome Editing surfactant deficiency viral vectors alveoli pulmonary disease AEC2 ATII |
| title | Gene Therapy Potential for Genetic Disorders of Surfactant Dysfunction |
| title_full | Gene Therapy Potential for Genetic Disorders of Surfactant Dysfunction |
| title_fullStr | Gene Therapy Potential for Genetic Disorders of Surfactant Dysfunction |
| title_full_unstemmed | Gene Therapy Potential for Genetic Disorders of Surfactant Dysfunction |
| title_short | Gene Therapy Potential for Genetic Disorders of Surfactant Dysfunction |
| title_sort | gene therapy potential for genetic disorders of surfactant dysfunction |
| topic | surfactant deficiency viral vectors alveoli pulmonary disease AEC2 ATII |
| url | https://www.frontiersin.org/articles/10.3389/fgeed.2021.785829/full |
| work_keys_str_mv | AT ashleylcooney genetherapypotentialforgeneticdisordersofsurfactantdysfunction AT ashleylcooney genetherapypotentialforgeneticdisordersofsurfactantdysfunction AT jenniferawambach genetherapypotentialforgeneticdisordersofsurfactantdysfunction AT patricklsinn genetherapypotentialforgeneticdisordersofsurfactantdysfunction AT patricklsinn genetherapypotentialforgeneticdisordersofsurfactantdysfunction AT paulbmccray genetherapypotentialforgeneticdisordersofsurfactantdysfunction AT paulbmccray genetherapypotentialforgeneticdisordersofsurfactantdysfunction |