{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T18:06:59Z","timestamp":1761934019383,"version":"build-2065373602"},"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T00:00:00Z","timestamp":1761868800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    It is estimated that ~2 billion people worldwide cannot afford even basic medicines.\n                    <jats:bold>B<\/jats:bold>\n                    ioreactor-produced\n                    <jats:bold>r<\/jats:bold>\n                    ecombinant\n                    <jats:bold>p<\/jats:bold>\n                    rotein\n                    <jats:bold>t<\/jats:bold>\n                    herapies (BRPTs), among the world\u2019s most-expensive medicines, have revolutionized treatment of a wide-spectrum of human-diseases, particularly the\u2009~\u20097,000 incurable, rare human single-protein, monogenic-deficiency diseases. Currently, BRPT are limited by toxicity, immunogenicity, short protein T\n                    <jats:sup>1<\/jats:sup>\n                    \/\n                    <jats:sub>2<\/jats:sub>\n                    s and high-cost, creating a worldwide access-gap between those who can afford BRPTs versus those who cannot. Fabry disease (FD) is a monogenic deficiency disease caused by pathogenic-variants of the galactosidase-a (GLA) gene. FD damages heart, kidneys, CNS, gastrointestinal tract, and eyes. State-of-the-art anti-FD therapy, hGLA enzyme-replacement-therapy (ERT), requires bi-weekly IV infusions lifelong, costing\u2009~\u2009$200,000 per-patient per-year. High-lifetime costs can cause significant numbers of FD patients to permanently discontinue hGLA-ERT, thereby accelerating FD progression, which can lead to premature-death. Subcutaneously administered plasmid DNA alone has not been previously reported to transfect subcutaneous fat. Here we show one\n                    <jats:bold>S<\/jats:bold>\n                    ubcutaneous\n                    <jats:bold>A<\/jats:bold>\n                    dministration of\n                    <jats:bold>H<\/jats:bold>\n                    EDGES\n                    <jats:bold>D<\/jats:bold>\n                    NA vectors\n                    <jats:bold>A<\/jats:bold>\n                    lone (\n                    <jats:bold>SAHDA<\/jats:bold>\n                    ) encoding the wildtype hGLA protein safely produces durable hGLA serum protein levels in the 1\u201310\u2009ng\/mL normal human hGLA range in immunocompetent mice. Unexpectedly, one administration of a highly-optimized SAHDA version encoding hGLA produced durable,\u2009~\u2009100-fold higher hGLA serum protein levels than the 10\u2009ng\/mL high-normal human level. Importantly, components of the SADHA platform can be simply-modified to control the level and duration of hGLA serum protein-levels produced over a broad temporal-range in mice. Furthermore, one SAHDA-based administration of a HEDGES DNA-vector encoding a highly-neutralizing anti-SARS-CoV-2 monoclonal antibody (mAb) safely produces long-term protective serum mAb levels in immunocompetent-mice. SAHDA offers multiple advantages over BRPT, including not requiring an intact cold-chain and being readily freeze-dried. This combination enables SAHDA\u2019s rapid deployment, then prolonged storage at ambient temperatures, even in equatorial-areas worldwide. SAHDA can readily be self-administered worldwide. It also obviates severe intravenous-infusion reactions. Taken-together, SAHDA may more effectively-, safely-, durably-, and cost-effectively-treat a spectrum of now poorly-treatable diseases worldwide.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0315041","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T18:01:51Z","timestamp":1761933711000},"page":"e0315041","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["One SQ HEDGES DNA vector only dose produces durable hGLA or anti-SARS-CoV-2 mAb therapeutic serum protein 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Jung","year":"2020","journal-title":"Arch Plast Surg"},{"issue":"5","key":"pone.0315041.ref033","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1002\/jmv.27588","article-title":"Omicron variant of SARS-CoV-2: Genomics, transmissibility, and responses to current COVID-19 vaccines","volume":"94","author":"Y Araf","year":"2022","journal-title":"J Med Virol"},{"key":"pone.0315041.ref034","doi-asserted-by":"crossref","first-page":"863234","DOI":"10.3389\/fimmu.2022.863234","article-title":"Immunoinformatic Design of a Multivalent Peptide Vaccine Against Mucormycosis: Targeting FTR1 Protein of Major Causative Fungi","volume":"13","author":"Y Araf","year":"2022","journal-title":"Front Immunol"},{"issue":"1","key":"pone.0315041.ref035","article-title":"SARS-CoV-2 and dengue virus co-infection: Epidemiology, pathogenesis, diagnosis, treatment, and management","volume":"33","author":"Noor-A-Afrin","year":"2023","journal-title":"Rev Med Virol"},{"issue":"12","key":"pone.0315041.ref036","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.3390\/vaccines10122145","article-title":"SARS-CoV-2: An Updated Review Highlighting Its Evolution and Treatments","volume":"10","author":"X Zhang","year":"2022","journal-title":"Vaccines (Basel)"},{"issue":"4","key":"pone.0315041.ref037","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2020.09.049","article-title":"A Therapeutic Non-self-reactive SARS-CoV-2 Antibody Protects from Lung Pathology in a COVID-19 Hamster Model","volume":"183","author":"J Kreye","year":"2020","journal-title":"Cell"},{"issue":"5","key":"pone.0315041.ref038","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1007\/s40259-018-0295-0","article-title":"Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities","volume":"32","author":"B Bittner","year":"2018","journal-title":"BioDrugs"},{"issue":"2","key":"pone.0315041.ref039","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s40259-020-00465-4","article-title":"Immunogenicity Challenges Associated with Subcutaneous Delivery of Therapeutic Proteins","volume":"35","author":"NL Jarvi","year":"2021","journal-title":"BioDrugs"},{"issue":"5","key":"pone.0315041.ref040","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1016\/j.xphs.2018.01.007","article-title":"Challenges and Opportunities for the Subcutaneous Delivery of Therapeutic Proteins","volume":"107","author":"MR Turner","year":"2018","journal-title":"J Pharm Sci"},{"issue":"5","key":"pone.0315041.ref041","doi-asserted-by":"crossref","first-page":"443","DOI":"10.4161\/mabs.1.5.9448","article-title":"Industrialization of mAb production technology: the bioprocessing industry at a crossroads","volume":"1","author":"B Kelley","year":"2009","journal-title":"MAbs"},{"issue":"1","key":"pone.0315041.ref042","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s00125-006-0496-9","article-title":"Committed subcutaneous preadipocytes are reduced in human obesity","volume":"50","author":"Y Tchoukalova","year":"2007","journal-title":"Diabetologia"},{"issue":"1","key":"pone.0315041.ref043","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1021\/js9801687","article-title":"PLGA microspheres containing plasmid DNA: preservation of supercoiled DNA via cryopreparation and carbohydrate stabilization","volume":"88","author":"S Ando","year":"1999","journal-title":"J Pharm Sci"},{"issue":"7","key":"pone.0315041.ref044","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1038\/sj.gt.3300947","article-title":"Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA","volume":"6","author":"F Liu","year":"1999","journal-title":"Gene 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