{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T17:59:37Z","timestamp":1761933577765,"version":"build-2065373602"},"reference-count":31,"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                    The great majority of human monogenic, single protein deficiency disease patients, who comprise ~\u20090.5% of the population, are incurable. When available, Enzyme Replacement Therapy (ERT) is current state-of-the art therapy for the vast majority of the subset of these diseases caused by enzyme deficiencies. For example, Fabry disease, caused by hemizygous- or heterozygous-pathogenic variants in GLA encoding human-galactocersbrosidase-\u03b1 (hGLA), is a rare, single protein-deficiency disease. Fabry patients require intravenous-administration of hGLA Enzyme Replacement Therapy (ERT) every two-weeks for-life. ERT costs ~\u2009$300,000 per-year and can cause frequent infusion reactions, which can be life-threatening. The very-high yearly GLA ERT costs, as well as the recurrent, life-threatening hGLA IV infusion-reactions experienced by some patients, can cause them to permanently-discontinue ERT. This can accelerate Fabry-disease progression, leading to premature-death. Therefore, new, more effective-, safe-, durable-, cost-effective, single deficient-protein replacement platforms are urgently-needed to more-effectively treat a wide-spectrum of these rare, monogenic single protein deficiency diseases. Here we demonstrate that one intravenous-administration of our 1\n                    <jats:sup>st<\/jats:sup>\n                    -generation HEDGES DNA-vector encoding wildtype-hGLA (T\n                    <jats:sup>1<\/jats:sup>\n                    \/\n                    <jats:sub>2<\/jats:sub>\n                    &lt;\u200920-minutes) produced hGLA serum-protein levels in the normal human 1,000-10,000\u2009pg\/ml range for only &lt;\u200914 days. We then-created our 2\n                    <jats:sup>nd<\/jats:sup>\n                    -generation HEDGES hGLA DNA-vector. One intravenous-administration of this DNA-vector produced durable (&gt;550 days) serum hGLA serum levels in the 1\u201310\u2009ng\/ml, thus increasing the duration of hGLA serum-protein levels produced by &gt;\u200938,100 fold versus administering bioreactor-produced, wildtype hGLA-protein. We also showed one intravenous-administration of our 1\n                    <jats:sup>st<\/jats:sup>\n                    -generation HEDGES DNA-vector encoding the wildtype human growth hormone (hGH) protein, (T\n                    <jats:sup>1<\/jats:sup>\n                    \/\n                    <jats:sub>2<\/jats:sub>\n                    &lt;\u200920-minutes), produced serum hGH levels in the 1\u201310\u2009ng\/ml for &gt;\u2009330 days, thus increasing the duration of hGLA serum-protein levels by &gt;\u200922,860 fold versus administering wildtype hGH-protein. Last, one intravenous-administration of our 2\n                    <jats:sup>nd<\/jats:sup>\n                    -generation HEDGES hGLA DNA-vector produced serum hGLA levels in the normal human 1\u201310\u2009ng\/ml range for &gt;\u2009160 days in GLA knockout-mice, a 2,800-fold increase versus wildtype hGLA-protein. hGLA-ERT produces major therapeutic-responses in GLA knockout-mice. These substantial ERT-responses in GLA knockout-mice have been shown to be accurately-recapitulated in Fabry patients. Thus, Fabry disease appears a promising-target for subsequent phase-1 HEDGES-based human clinical trials.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0318977","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T17:56:52Z","timestamp":1761933412000},"page":"e0318977","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["One IV HEDGES DNA vector administration encoding hGLA or hGH produces durable hGLA and hGH serum lvels in immunocompetent mice"],"prefix":"10.1371","volume":"20","author":[{"given":"Alice","family":"Ye","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marissa","family":"Mack","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Ursu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9857-2506","authenticated-orcid":true,"given":"Stephen","family":"Chmura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4177-4590","authenticated-orcid":true,"given":"Robert","family":"Steiner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"Heath","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chakkrapong","family":"Handumrongkul","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9929-6267","authenticated-orcid":true,"given":"Robert","family":"Debs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,10,31]]},"reference":[{"key":"pone.0318977.ref001","doi-asserted-by":"crossref","first-page":"121108","DOI":"10.1016\/j.biomaterials.2021.121108","article-title":"Gene 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