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bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.05.22.594822
preprint
2
Article
Development and Initial Characterization of Pigs with DNAI1 Mutations and Primary Ciliary Dyskinesia
Abou Alaiwa Mahmoud A. http://orcid.org/0000-0003-4525-0217

Hilkin Brie M.
Price Margaret P.
Gansemer Nicholas D.
Rector Michael R.
Stroik Mal R.
Powers Linda S.
Whitworth Kristin M. http://orcid.org/0000-0001-9959-108X

Samuel Melissa S.
Jain Akansha http://orcid.org/0000-0002-6991-9256

Ostedgaard Lynda S. http://orcid.org/0000-0001-7717-3442

Ernst Sarah E.
Philibert Winter
Boyken Linda D.
Moninger Thomas O.
Karp Phillip H.
Hornick Douglas B.
Sinn Patrick L. http://orcid.org/0000-0002-9746-966X

Fischer Anthony J. http://orcid.org/0000-0002-7179-6400

Pezzulo Alejandro A. http://orcid.org/0000-0001-7544-5109

McCray Paul B. http://orcid.org/0000-0002-4067-577X

Meyerholz David K. http://orcid.org/0000-0003-1552-3253

Zabner Joseph http://orcid.org/0000-0002-9606-1339

Prather Randy S. http://orcid.org/0000-0002-6012-4035

Welsh Michael J. http://orcid.org/0000-0002-1646-6206

Stoltz David A. http://orcid.org/0000-0003-0893-9015

21 8 2024
2024.05.22.594822https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.05.22.594822
nihpp-2024.05.22.594822.pdf
ABSTRACT

Mutations in more than 50 different genes cause primary ciliary dyskinesia (PCD) by disrupting the activity of motile cilia that facilitate mucociliary transport (MCT). Knowledge of PCD has come from studies identifying disease-causing mutations, characterizing structural cilia abnormalities, finding genotype-phenotype relationships, and studying the cell biology of cilia. Despite these important findings, we still lack effective treatments and people with PCD have significant pulmonary impairment. As with many other diseases, a better understanding of pathogenic mechanisms may lead to effective treatments. To pursue disease mechanisms, we used CRISPR-Cas9 to develop a PCD pig with a disrupted DNAI1 gene. PCD pig airway cilia lacked the outer dynein arm and had impaired beating. MCT was impaired under both baseline conditions and after cholinergic stimulation in PCD pigs. Neonatal PCD pigs developed neonatal respiratory distress with evidence of atelectasis, air trapping, and airway mucus obstruction. Despite airway mucus accumulation, lung bacterial counts were similar between neonatal wild-type and PCD pigs. Sinonasal disease was present in all neonatal PCD pigs. Older PCD pigs developed worsening airway mucus obstruction, inflammation, and bacterial infection. This pig model closely mimics the disease phenotype seen in people with PCD and can be used to better understand the pathophysiology of PCD airway disease.
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