Browsing by Author "Walsh, Matthew C."

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    Inhibition of IFNAR-JAK signaling enhances tolerability and transgene expression of systemic non-viral DNA delivery
    (Elsevier, 2025-03-05) Senapati, Sujata; Bertolini, Thais B.; Minnier, Michael A.; Yazicioglu, Mustafa N.; Markusic, David M.; Zhang, Rui; Wicks, Joan; Nahvi, Ali; Herzog, Roland W.; Walsh, Matthew C.; Cejas, Pedro J.; Armour, Sean M.; Pediatrics, School of Medicine
    Lipid nanoparticles (LNPs) have demonstrated significant therapeutic value for non-viral delivery of mRNA and siRNA. While there is considerable interest in utilizing LNPs for delivering DNA (DNA-LNPs) to address a broad range of genetic disorders, acute inflammatory responses pose significant safety concerns and limit transgene expression below therapeutically relevant levels. However, the mechanisms and immune signaling pathways underlying DNA-LNP-triggered inflammatory responses are not well characterized. Through the use of gene-targeted mouse models, we have identified cGAS-STING and interferon-α/β receptor (IFNAR) pathways as major mediators of acute inflammation triggered by systemic delivery of DNA-LNPs. cGAS-STING activation induces expression of numerous JAK-STAT-activating cytokines, and we show that treatment of mice with the JAK inhibitors ruxolitinib or baricitinib significantly improves tolerability to systemically delivered DNA-LNPs. Furthermore, specific inhibition of IFNAR signaling enhances both DNA-LNP tolerability and transgene expression. Utilization of JAK inhibitors or IFNAR blockade represent promising strategies for enhancing the safety and efficacy of non-viral DNA delivery for gene therapy.