Optimized AAV capsids robustly transduce airway epithelial cells

Ashley L. Cooney; Yong Hong Chen; Brian C. Lewandowski; Shakayla Lamer; Griffin Boysen; Katarina Kulhankova; Amber Vu; Priyanka Newase; Patrick L. Sinn; Beverly L. Davidson; Paul B. McCray

doi:10.64898/2026.05.10.723853

Back

Optimized AAV capsids robustly transduce airway epithelial cells

Preprint

Open access

Optimized AAV capsids robustly transduce airway epithelial cells

Ashley L. Cooney, Yong Hong Chen, Brian C. Lewandowski, Shakayla Lamer, Griffin Boysen, Katarina Kulhankova, Amber Vu, Priyanka Newase, Patrick L. Sinn, Beverly L. Davidson, …

bioRxiv

Cold Spring Harbor Laboratory Preprints

05/11/2026

DOI: 10.64898/2026.05.10.723853

PMCID: PMC13193003

PMID: 42182483

Files and links (1)

url

https://doi.org/10.64898/2026.05.10.723853View

Preprint (Author's original) This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Gene therapies have demonstrated transformative potential for a range of genetic disorders, including immunodeficiencies, hematopoietic conditions, and neuromuscular diseases. However, the application of these approaches to cystic fibrosis (CF) and other airway diseases remains constrained by the challenge of efficient gene delivery to target epithelial cells. Adeno-associated virus (AAV) vectors are widely used for in vivo gene delivery due to their favorable safety profile and capacity for long-term transgene expression in non-dividing cells. Nonetheless, current AAV capsids require high doses to achieve therapeutic efficacy in the airways, raising safety concerns. Here we report the development of novel AAV capsid variants with markedly enhanced transduction efficiency of airway epithelial cells. Using unbiased peptide-modified AAV libraries and round-over-round screening in well-differentiated primary cultures of human airway epithelia (HAE), we identified 20 novel capsids that efficiently transduced cells at doses 10- to 100-fold lower than those required by existing vectors (termed AAV-AE). These variants demonstrated high transgene expression in HAE, primary human basal cells, tracheal explants from nonhuman primates, and murine airways in vivo. These optimized AAV capsids represent a significant advancement in pulmonary gene therapy, offering a versatile platform for the delivery of gene addition and editing reagents to treat CF and other respiratory diseases.

Details

Title: Subtitle: Optimized AAV capsids robustly transduce airway epithelial cells
Creators: Ashley L. Cooney - University of Iowa
Yong Hong Chen - Children's Hospital of Philadelphia
Brian C. Lewandowski - Children's Hospital of Philadelphia
Shakayla Lamer - University of Iowa
Griffin Boysen - University of Iowa
Katarina Kulhankova - University of Iowa, Stead Family Department of Pediatrics
Amber Vu - University of Iowa
Priyanka Newase - University of Iowa
Patrick L. Sinn - University of Iowa
Beverly L. Davidson - Children's Hospital of Philadelphia
Paul B. McCray - University of Iowa
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.64898/2026.05.10.723853
PMID: 42182483
PMCID: PMC13193003
eISSN: 2692-8205
Publisher: Cold Spring Harbor Laboratory Preprints
Language: English
Date posted: 05/11/2026
Academic Unit: Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Internal Medicine
Record Identifier: 9985164610002771

Metrics

1 Record Views