{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:06:45Z","timestamp":1791295605239,"version":"4.1.0"},"reference-count":38,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:00:00Z","timestamp":1659312000000},"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":["Nucleic Acid Therapeutics"],"published-print":{"date-parts":[[2022,8,1]]},"abstract":"<jats:p>\n                    Mongersen is a 21-mer antisense oligonucleotide designed to downregulate Mothers against decapentaplegic homolog 7 (SMAD7) expression to treat Crohn's disease. Mongersen was manufactured in numerous batches at different scales during several years of clinical development, which all appeared identical, using common physicochemical analytical techniques, while only phosphorous-31 nuclear magnetic resonance (\n                    <jats:sup>31<\/jats:sup>\n                    P-NMR) in solution showed marked differences. Close-up analysis of 27 mongersen batches revealed marked differences in SMAD7 downregulation in a cell-based assay. Principal component analysis of\n                    <jats:sup>31<\/jats:sup>\n                    P-NMR profiles showed strong correlation with SMAD7 downregulation and, therefore, with pharmacological efficacy\n                    <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                    . Mongersen contains 20 phosphorothioate (PS) linkages, whose chirality (Rp\/Sp) was not controlled during manufacturing. A different diastereomeric composition throughout batches would lead to superimposable analytical data, but to distinct\n                    <jats:sup>31<\/jats:sup>\n                    P-NMR profiles, as indeed we found. We tentatively suggest that this may be the origin of different biological activity. As similar manifolds are expected for other PS-based oligonucleotides, the protocol described here provides a general method to identify PS chirality issues and a chemometric tool to score each preparation for this elusive feature.\n                  <\/jats:p>","DOI":"10.1089\/nat.2021.0089","type":"journal-article","created":{"date-parts":[[2022,3,9]],"date-time":"2022-03-09T15:22:40Z","timestamp":1646839360000},"page":"312-320","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":30,"title":["Inhomogeneous Diastereomeric Composition of Mongersen Antisense Phosphorothioate Oligonucleotide Preparations and Related Pharmacological Activity Impairment"],"prefix":"10.1177","volume":"32","author":[{"given":"Lorenzo","family":"Arrico","sequence":"first","affiliation":[{"name":"Dipartimento di Chimica e Chimica Industriale, Universit\u00e0 di Pisa, Pisa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmine","family":"Stolfi","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina dei Sistemi, Universit\u00e0 di Roma \u201cTor Vergata,\u201d Rome, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Marafini","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina dei Sistemi, Universit\u00e0 di Roma \u201cTor Vergata,\u201d Rome, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Monteleone","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina dei Sistemi, Universit\u00e0 di Roma \u201cTor Vergata,\u201d Rome, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Demartis","sequence":"additional","affiliation":[{"name":"PPM Services SA, Morbio Inferiore, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Bellinvia","sequence":"additional","affiliation":[{"name":"PPM Services SA, Morbio Inferiore, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Viti","sequence":"additional","affiliation":[{"name":"PPM Services SA, Morbio Inferiore, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Mcnulty","sequence":"additional","affiliation":[{"name":"Nogra Pharma Limited, Dublin, Ireland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Cabani","sequence":"additional","affiliation":[{"name":"Regulatory Pharma Net s.r.l., Pisa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Falezza","sequence":"additional","affiliation":[{"name":"Regulatory Pharma Net s.r.l., Pisa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2347-2150","authenticated-orcid":false,"given":"Lorenzo","family":"Di Bari","sequence":"additional","affiliation":[{"name":"Dipartimento di Chimica e Chimica Industriale, Universit\u00e0 di Pisa, Pisa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2022,8,4]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00162-z"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-020-0075-7"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.03.004"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3765"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b00551"},{"key":"e_1_3_4_7_2","first-page":"117","volume":"10","author":"Eckstein F","year":"2000","unstructured":"Eckstein F. 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