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Moderate Heat-Assisted Gene Electrotransfer as a Potential Delivery Approach for Protein Replacement Therapy through the Skin

Gene-based approaches for protein replacement therapies have the potential to reduce the number of administrations. Our previous work demonstrated that expression could be enhanced and/or the applied voltage reduced by preheating the tissue prior to pulse administration. In the current study, we uti...

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Autores principales: Edelblute, Chelsea, Mangiamele, Cathryn, Heller, Richard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624362/
https://www.ncbi.nlm.nih.gov/pubmed/34834323
http://dx.doi.org/10.3390/pharmaceutics13111908
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author Edelblute, Chelsea
Mangiamele, Cathryn
Heller, Richard
author_facet Edelblute, Chelsea
Mangiamele, Cathryn
Heller, Richard
author_sort Edelblute, Chelsea
collection PubMed
description Gene-based approaches for protein replacement therapies have the potential to reduce the number of administrations. Our previous work demonstrated that expression could be enhanced and/or the applied voltage reduced by preheating the tissue prior to pulse administration. In the current study, we utilized our 16-pin multi-electrode array (MEA) and incorporated nine optical fibers, connected to an infrared laser, between each set of four electrodes to heat the tissue to 43 °C. For proof of principle, a guinea pig model was used to test delivery of reporter genes. We observed that when the skin was preheated, it was possible to achieve the same expression levels as gene electrotransfer without preheating, but with a 23% reduction of applied voltage or a 50% reduction of pulse number. With respect to expression distribution, preheating allowed for delivery to the deep dermis and muscle. This suggested that this cutaneous delivery approach has the potential to achieve expression in the systemic circulation, thus this protocol was repeated using a plasmid encoding Human Factor IX. Elevated Factor IX serum protein levels were detected by ELISA up to 100 days post gene delivery. Further work will involve optimizing protein levels and scalability in an effort to reduce application frequency.
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spelling pubmed-86243622021-11-27 Moderate Heat-Assisted Gene Electrotransfer as a Potential Delivery Approach for Protein Replacement Therapy through the Skin Edelblute, Chelsea Mangiamele, Cathryn Heller, Richard Pharmaceutics Article Gene-based approaches for protein replacement therapies have the potential to reduce the number of administrations. Our previous work demonstrated that expression could be enhanced and/or the applied voltage reduced by preheating the tissue prior to pulse administration. In the current study, we utilized our 16-pin multi-electrode array (MEA) and incorporated nine optical fibers, connected to an infrared laser, between each set of four electrodes to heat the tissue to 43 °C. For proof of principle, a guinea pig model was used to test delivery of reporter genes. We observed that when the skin was preheated, it was possible to achieve the same expression levels as gene electrotransfer without preheating, but with a 23% reduction of applied voltage or a 50% reduction of pulse number. With respect to expression distribution, preheating allowed for delivery to the deep dermis and muscle. This suggested that this cutaneous delivery approach has the potential to achieve expression in the systemic circulation, thus this protocol was repeated using a plasmid encoding Human Factor IX. Elevated Factor IX serum protein levels were detected by ELISA up to 100 days post gene delivery. Further work will involve optimizing protein levels and scalability in an effort to reduce application frequency. MDPI 2021-11-11 /pmc/articles/PMC8624362/ /pubmed/34834323 http://dx.doi.org/10.3390/pharmaceutics13111908 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Edelblute, Chelsea
Mangiamele, Cathryn
Heller, Richard
Moderate Heat-Assisted Gene Electrotransfer as a Potential Delivery Approach for Protein Replacement Therapy through the Skin
title Moderate Heat-Assisted Gene Electrotransfer as a Potential Delivery Approach for Protein Replacement Therapy through the Skin
title_full Moderate Heat-Assisted Gene Electrotransfer as a Potential Delivery Approach for Protein Replacement Therapy through the Skin
title_fullStr Moderate Heat-Assisted Gene Electrotransfer as a Potential Delivery Approach for Protein Replacement Therapy through the Skin
title_full_unstemmed Moderate Heat-Assisted Gene Electrotransfer as a Potential Delivery Approach for Protein Replacement Therapy through the Skin
title_short Moderate Heat-Assisted Gene Electrotransfer as a Potential Delivery Approach for Protein Replacement Therapy through the Skin
title_sort moderate heat-assisted gene electrotransfer as a potential delivery approach for protein replacement therapy through the skin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624362/
https://www.ncbi.nlm.nih.gov/pubmed/34834323
http://dx.doi.org/10.3390/pharmaceutics13111908
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