Gene Therapeutics for Surfactant Dysfunction Disorders: Targeting the Alveolar Type 2 Epithelial Cell
Abstract
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.
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Copyright 2022, by Mary Ann Liebert, Inc., publishers.
History
Published online: 17 October 2022
Published in print: October 2022
Published ahead of production: 27 September 2022
Accepted: 29 August 2022
Received: 8 June 2022
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Authors' Contributions
S.S. contributed to conceptualization, writing—original draft, review and editing. K.-D.A. and J.A.W. performed writing—original draft, review and editing. M.P.L. provided conceptualization, supervision, writing—review and editing.
Author Disclosure
S.S. and M.P.L. are employees of Spirovant Sciences, Inc. All other authors have no competing financial interests.
Funding Information
This work was supported in part by an I.M. Rosenzweig Junior Investigator Award from The Pulmonary Fibrosis Foundation and an Integrated Pilot Grant Award through Boston University Clinical & Translational Science Institute (1UL1TR001430) to K.-D.A., NIH NHLBI (R01HL149853 and U01HL13475) and Children's Discovery Institute grants to J.A.W.
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