{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T21:15:21Z","timestamp":1777670121986,"version":"3.51.4"},"reference-count":25,"publisher":"SAGE Publications","issue":"13-14","license":[{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:p>\n                    Biological bypass through induced angiogenesis by vascular endothelial growth factor D (VEGF-D) gene therapy (GT) is a new concept for the treatment of cardiac ischemia. Serotype 5 adenoviruses are used in the clinical trials for transferring the VEGF-D cDNA into the ischemic myocardium. However, the presence of replication-competent vectors in the adenovirus products is a widely recognized problem that may pose a potential safety risk to the treated patients. We compared three different VEGF-D GT production lots containing different levels of replication-competent adenoviruses (RCA) tested in 3\u2009\u00d7\u200910\n                    <jats:sup>10<\/jats:sup>\n                    viral particles (vp): &lt;10 RCA (VEGF-D L-RCA1), 10\u2013100 RCA (VEGF-D H-RCA2), and 100\u2013200 RCA (VEGF-D H-RCA3), as measured by a novel droplet digital polymerase chain reaction (PCR) RCA assay in a preclinical rabbit model (\n                    <jats:italic toggle=\"yes\">n<\/jats:italic>\n                    \u2009=\u200921). \u03b2-galactosidase encoding nonclinical-grade preparation was used as a nonangiogenic control. Each preparation was injected into the right semimembranosus muscle using dose of 1\u2009\u00d7\u200910\n                    <jats:sup>11<\/jats:sup>\n                    vp. Efficacy of the products was tested by the combination of contrast pulse sequencing ultrasound and modified Miles assay as well as quantifying the total cross-sectional area of capillaries. Safety, immunogenicity, toxicity, biodistribution, and shedding were assessed by general histology, serial measurements of C-reactive protein, white blood cell count and body temperature as well as using quantitative real-time PCR with primers targeted to the VEGF-D and replication-permitting E1 sequences. We found no significant differences in the efficacy or safety between the study groups. Most importantly, no detectable presence of RCA-specific E1 sequence was found in any samples tested, indicating that no detectable vector replication took place\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    . We conclude that relatively low levels of RCA in adenoviral GT products may not be as important major safety issue as previously anticipated.\n                  <\/jats:p>","DOI":"10.1089\/hum.2020.299","type":"journal-article","created":{"date-parts":[[2020,12,29]],"date-time":"2020-12-29T00:57:06Z","timestamp":1609203426000},"page":"761-770","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":7,"title":["Efficacy and Safety of Clinical-Grade Human Vascular Endothelial Growth Factor-D\n                    <sup>\u0394N\u0394C<\/sup>\n                    Gene Therapy Containing Residual Replication-Competent Adenoviruses"],"prefix":"10.1177","volume":"32","author":[{"given":"Aleksi J.","family":"Leikas","sequence":"first","affiliation":[{"name":"Heart Center, Kuopio University Hospital, Kuopio, Finland"},{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland"},{"name":"Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nihay","family":"Laham-Karam","sequence":"additional","affiliation":[{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eline","family":"Agtereek","sequence":"additional","affiliation":[{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanna M.","family":"Peltonen","sequence":"additional","affiliation":[{"name":"FinVector Oy, Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tuomas","family":"Selander","sequence":"additional","affiliation":[{"name":"Science Service Center, Kuopio University Hospital, Kuopio, Finland."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Korpisalo","sequence":"additional","affiliation":[{"name":"Heart Center, Kuopio University Hospital, Kuopio, Finland"},{"name":"Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lari","family":"Holappa","sequence":"additional","affiliation":[{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juha E. K.","family":"Hartikainen","sequence":"additional","affiliation":[{"name":"Heart Center, Kuopio University Hospital, Kuopio, Finland"},{"name":"Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tommi","family":"Heikura","sequence":"additional","affiliation":[{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seppo","family":"Yl\u00e4-Herttuala","sequence":"additional","affiliation":[{"name":"Heart Center, Kuopio University Hospital, Kuopio, Finland"},{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland"},{"name":"Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2021,7,19]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-012017-043332"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2012.04.008"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2017.03.027"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehx352"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000070540.80780.92"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.3015"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-800276-6.00004-8"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3300902"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3301301"},{"key":"e_1_3_5_11_2","unstructured":"U.S. Department of Health and Human Services . Food and Drug Administration . Center for Biologics Evaluation and Research. Chemistry manufacturing and control (CMC) information for human gene therapy investigational new drug applications (INDs): guidance for industry. 2020. https:\/\/www.fda.gov\/media\/113760\/download (last accessed July1 2020)."},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-4347(00)00557-0"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.1994.5.12-1485"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2003.09.001"},{"key":"e_1_3_5_15_2","unstructured":"Peltonen HM Mykk\u00e4nen J Hassinen M. Gene Therapy Vector Contamination Assay. US Patent Application 20190292609 2019."},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000073584.46059.E3"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2016-309373"},{"key":"e_1_3_5_18_2","unstructured":"U.S. Department of Health and Human Services. Food and Drug Administration. Center for Biologics Evaluation and Research. 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