{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Ning K"],"funding":["University of Iowa","NIAID NIH HHS","NIEHS NIH HHS","National Institutes of Health","NIAID","NIDDK"],"pagination":["101115"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10568418"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["31"],"pubmed_abstract":["Adeno-associated virus 2.5T (AAV2.5T) was selected from the directed evolution of AAV capsid library in human airway epithelia. This study found that recombinant AAV2.5T (rAAV2.5T) transduction of well-differentiated primary human airway epithelia induced a DNA damage response (DDR) characterized by the phosphorylation of replication protein A32 (RPA32), histone variant H2AX (H2A histone family member X), and all three phosphatidylinositol 3-kinase-related kinases: ataxia telangiectasia mutated kinase, ataxia telangiectasia and Rad3-related kinase (ATR), and DNA-dependent protein kinase catalytic subunit (DNA-PK<sub>cs</sub>). While suppressing the expression of ATR by a specific pharmacological inhibitor or targeted gene silencing inhibited rAAV2.5T transduction, DNA-PK<sub>cs</sub> inhibition or targeted gene silencing significantly increased rAAV2.5T transgene expression. Notably, DNA-PK<sub>cs</sub> inhibitors worked as a \"booster\" to further increase rAAV2.5T transgene expression after treatment with doxorubicin and did not compromise epithelial integrity. Thus, our study provides evidence that DDR is associated with rAAV transduction in well-differentiated human airway epithelia, and DNA-PK<sub>cs</sub> inhibition has the potential to boost rAAV transduction. These findings highlight that the application of DDR inhibition-associated pharmacological interventions has the potential to increase rAAV transduction and thus to reduce the required vector dose."],"journal":["Molecular therapy. Methods & clinical development"],"pubmed_title":["Inhibition of DNA-dependent protein kinase catalytic subunit boosts rAAV transduction of polarized human airway epithelium."],"pmcid":["PMC10568418"],"funding_grant_id":["P30 ES005605","AI150877","R01 AI150877","S10 OD 023625","AI156448","DK054759"],"pubmed_authors":["Qiu J","Cheng F","Yan Z","Feng Z","Zhang X","Ning K","Kuz CA","McFarlin S","Park SY","Hao S","Engelhardt JF"],"additional_accession":[]},"is_claimable":false,"name":"Inhibition of DNA-dependent protein kinase catalytic subunit boosts rAAV transduction of polarized human airway epithelium.","description":"Adeno-associated virus 2.5T (AAV2.5T) was selected from the directed evolution of AAV capsid library in human airway epithelia. This study found that recombinant AAV2.5T (rAAV2.5T) transduction of well-differentiated primary human airway epithelia induced a DNA damage response (DDR) characterized by the phosphorylation of replication protein A32 (RPA32), histone variant H2AX (H2A histone family member X), and all three phosphatidylinositol 3-kinase-related kinases: ataxia telangiectasia mutated kinase, ataxia telangiectasia and Rad3-related kinase (ATR), and DNA-dependent protein kinase catalytic subunit (DNA-PK<sub>cs</sub>). While suppressing the expression of ATR by a specific pharmacological inhibitor or targeted gene silencing inhibited rAAV2.5T transduction, DNA-PK<sub>cs</sub> inhibition or targeted gene silencing significantly increased rAAV2.5T transgene expression. Notably, DNA-PK<sub>cs</sub> inhibitors worked as a \"booster\" to further increase rAAV2.5T transgene expression after treatment with doxorubicin and did not compromise epithelial integrity. Thus, our study provides evidence that DDR is associated with rAAV transduction in well-differentiated human airway epithelia, and DNA-PK<sub>cs</sub> inhibition has the potential to boost rAAV transduction. These findings highlight that the application of DDR inhibition-associated pharmacological interventions has the potential to increase rAAV transduction and thus to reduce the required vector dose.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Dec","modification":"2024-11-06T01:32:15.917Z","creation":"2024-11-06T01:32:15.917Z"},"accession":"S-EPMC10568418","cross_references":{"pubmed":["37841417"],"doi":["10.1016/j.omtm.2023.101115"]}}