{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T09:56:35Z","timestamp":1753869395069,"version":"3.41.2"},"reference-count":52,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2017,8,25]],"date-time":"2017-08-25T00:00:00Z","timestamp":1503619200000},"content-version":"vor","delay-in-days":24,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Gene Medicine"],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Rheumatoid arthritis (RA) is a symmetric inflammatory polyarthritis associated with high concentrations of pro\u2010inflammatory, cytokines including tumor necrosis factor (TNF)\u2010\u03b1. Adalimumab is a monoclonal antibody (mAb) that binds TNF\u2010\u03b1, and is widely used to treat RA. Despite its proven clinical efficacy, adalimumab and other therapeutic mAbs have disadvantages, including the requirement for repeated bolus injections and the appearance of treatment limiting anti\u2010drug antibodies. To address these issues, we have developed an innovative <jats:italic>ex vivo<\/jats:italic> gene therapy approach, termed transduced autologous restorative gene therapy (TARGT), to produce and secrete adalimumab for the treatment of RA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Helper\u2010dependent (HD) adenovirus vector containing adalimumab light and heavy chain coding sequences was used to transduce microdermal tissues and cells of human and mouse origin <jats:italic>ex vivo<\/jats:italic>, rendering sustained secretion of active adalimumab. The genetically engineered tissues were subsequently implanted in a mouse model of RA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Transduced human microdermal tissues implanted in SCID mice demonstrated 49\u00a0days of secretion of active adalimumab in the blood, at levels of tens of microgram per milliliter. In addition, transduced autologous dermal cells were implanted in the RA mouse model and demonstrated statistically significant amelioration in RA symptoms compared to na\u00efve cell implantation and were similar to recombinant adalimumab bolus injections.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The results of the present study report microdermal tissues engineered to secrete active adalimumab as a proof of concept for sustained secretion of antibody from the novel <jats:italic>ex vivo<\/jats:italic> gene therapy TARGT platform. This technology may now be applied to a range of antibodies for the therapy of other diseases.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jgm.2965","type":"journal-article","created":{"date-parts":[[2017,6,28]],"date-time":"2017-06-28T21:06:35Z","timestamp":1498683995000},"source":"Crossref","is-referenced-by-count":4,"title":["Sustained secretion of anti\u2010tumor necrosis factor \u03b1 monoclonal antibody from <i>ex vivo<\/i> genetically engineered dermal tissue demonstrates therapeutic activity in mouse model of rheumatoid arthritis"],"prefix":"10.1002","volume":"19","author":[{"given":"Inbal","family":"Zafir\u2010Lavie","sequence":"first","affiliation":[{"name":"Medgenics Medical Israel, Ltd  Misgav Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reem","family":"Miari","sequence":"additional","affiliation":[{"name":"Medgenics Medical Israel, Ltd  Misgav Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shay","family":"Sherbo","sequence":"additional","affiliation":[{"name":"Medgenics Medical Israel, Ltd  Misgav Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simi","family":"Krispel","sequence":"additional","affiliation":[{"name":"Medgenics Medical Israel, Ltd  Misgav Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Osnat","family":"Tal","sequence":"additional","affiliation":[{"name":"Medgenics Medical Israel, Ltd  Misgav Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atar","family":"Liran","sequence":"additional","affiliation":[{"name":"Medgenics Medical Israel, Ltd  Misgav Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamar","family":"Shatil","sequence":"additional","affiliation":[{"name":"Medgenics Medical Israel, Ltd  Misgav Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felix","family":"Badinter","sequence":"additional","affiliation":[{"name":"Medgenics Medical Israel, Ltd  Misgav Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haim","family":"Goltsman","sequence":"additional","affiliation":[{"name":"Medgenics Medical Israel, Ltd  Misgav Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nir","family":"Shapir","sequence":"additional","affiliation":[{"name":"Medgenics Medical Israel, Ltd  Misgav Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Itai","family":"Benhar","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Biotechnology, The George S. Wise Faculty of Life Sciences Tel\u2010Aviv University  Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Garry A.","family":"Neil","sequence":"additional","affiliation":[{"name":"Aevi Genomic Medicine, Inc.  Wayne Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amos","family":"Panet","sequence":"additional","affiliation":[{"name":"Department of Biochemistry (IMRIC) The Hebrew University\u2010Hadassah Medical School  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,8,25]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40259-013-0021-x"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.19.1.163"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri802"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199707173370301"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(94)90628-9"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.58.2008.i70"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt0994-899"},{"key":"e_1_2_6_9_1","unstructured":"SalfeldJG AllenDJ HoogenboomHRJM et al.Human Antibodies that Bind Human TNF\u03b1. Google Patents 2000."},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.10697"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.3109\/9780203624388-5"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3229"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2004.08.002"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2015.1008351"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1001\/archderm.144.9.1190"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-012-9340-y"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.2174\/15665232113139990025"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2013.11.041"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2015.05.003"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2007.08.034"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2005.03.023"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.740"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1089\/humc.2015.125"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1606202"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(91)90434-D"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2003.08.014"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1087"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0063247"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-59745-237-3_3"},{"key":"e_1_2_6_30_1","doi-asserted-by":"crossref","unstructured":"SeluanovA VaidyaA GorbunovaV.Establishing primary adult fibroblast cultures from rodents.2010;44:e2033.","DOI":"10.3791\/2033"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1991.tb04978.x"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar1179"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-82-5-1013"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku082"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2013.1424"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3834"},{"key":"e_1_2_6_37_1","unstructured":"US Food and Drug Administration CfDEaR.Drugs@FDA: FDA Approved Drug Products.http:\/\/www.accessdata.fda.gov\/scripts\/cder\/daf\/index.cfm?event=BasicSearch.process[Accessed 4 April 2017]."},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2005.01.001"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15818"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2005.16.1"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/v2091886"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2623"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms160510578"},{"key":"e_1_2_6_44_1","first-page":"419","article-title":"Adalimumab in rheumatoid arthritis treatment: A systematic review and meta\u2010analysis of randomized clinical trials","volume":"53","author":"Machado MA","year":"2013","journal-title":"Rev Bras Reumatol"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1586\/egh.11.81"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-015-0503-x"},{"key":"e_1_2_6_47_1","first-page":"1406","article-title":"Adalimumab (Humira) for the treatment of rheumatoid arthritis","volume":"78","author":"Welch B","year":"2008","journal-title":"Am Fam Physician"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-207978"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1517\/14740338.4.4.637"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2011.406"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2009.03.012"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1111\/apt.12507"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1586\/1744666X.2014.926219"}],"container-title":["The Journal of Gene Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjgm.2965","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jgm.2965","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,9]],"date-time":"2023-09-09T19:00:43Z","timestamp":1694286043000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jgm.2965"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8]]},"references-count":52,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2017,8]]}},"alternative-id":["10.1002\/jgm.2965"],"URL":"https:\/\/doi.org\/10.1002\/jgm.2965","archive":["Portico"],"relation":{},"ISSN":["1099-498X","1521-2254"],"issn-type":[{"type":"print","value":"1099-498X"},{"type":"electronic","value":"1521-2254"}],"subject":[],"published":{"date-parts":[[2017,8]]},"article-number":"e2965"}}