Browsing by Subject "Delivery strategies"

Now showing 1 - 2 of 2
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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.
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    Topical tissue nanotransfection of Prox1 is effective in the prophylactic management of lymphedema
    (Elsevier, 2024-01-18) Mohan, Ganesh; Khan, Imran; Neumann, Colby R.; Jorge, Miguel D.; Ahmed, Shahnur; Hulsman, Luci; Sinha, Mithun; Gordillo, Gayle M.; Sen, Chandan K.; Hassanein, Aladdin H.; Surgery, School of Medicine
    Lymphedema is chronic limb swelling resulting from lymphatic dysfunction. There is no cure for the disease. Clinically, a preventive surgical approach called immediate lymphatic reconstruction (ILR) has gained traction. Experimental gene-based therapeutic approaches (e.g., using viral vectors) have had limited translational applicability. Tissue nanotransfection (TNT) technology uses a direct, transcutaneous nonviral vector, gene delivery using a chip with nanochannel poration in response to a rapid (<100 ms) focused electric field. The purpose of this study was to experimentally prevent lymphedema using focal delivery of a specific gene Prox1 (a master regulator of lymphangiogenesis). TNT was applied to the previously optimized lymphedematous mice tail (day 0) directly at the surgical site with genetic cargo loaded into the TNT reservoir: group I (sham) was given pCMV6 (expression vector backbone alone) and group II was treated with pCMV6-Prox1. Group II mice had decreased tail volume (47.8%) compared to sham and greater lymphatic clearance on lymphangiography. Immunohistochemistry showed greater lymphatic vessel density and RNA sequencing exhibited reduced inflammatory markers in group II compared to group I. Prox1 prophylactically delivered using TNT to the surgical site on the day of injury decreased the manifestations of lymphedema in the murine tail model compared to control.