{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T03:54:36Z","timestamp":1792814076200,"version":"4.5.0"},"reference-count":39,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"691","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2023,4,12]]},"abstract":"<jats:p>\n                    Diffuse midline gliomas (DMGs) are pediatric high-grade brain tumors in the thalamus, midbrain, or pons; the latter subgroup are termed diffuse intrinsic pontine gliomas (DIPG). The brain stem location of these tumors limits the clinical management of DIPG, resulting in poor outcomes for patients. A heterozygous, somatic point mutation in one of two genes coding for the noncanonical histone H3.3 is present in most DIPG tumors. This dominant mutation in the\n                    <jats:italic>H3-3A<\/jats:italic>\n                    gene results in replacement of lysine 27 with methionine (K27M) and causes a global reduction of trimethylation on K27 of all wild-type histone H3 proteins, which is thought to be a driving event in gliomagenesis. In this study, we designed and systematically screened 2\u2032-\n                    <jats:italic>O<\/jats:italic>\n                    -methoxyethyl phosphorothioate antisense oligonucleotides (ASOs) that direct RNase H\u2013mediated knockdown of\n                    <jats:italic>H3-3A<\/jats:italic>\n                    mRNA. We identified a lead ASO that effectively reduced\n                    <jats:italic>H3-3A<\/jats:italic>\n                    mRNA and H3.3K27M protein and restored global H3K27 trimethylation in patient-derived neurospheres. We then tested the lead ASO in two mouse models of DIPG: an immunocompetent mouse model using transduced mutant human\n                    <jats:italic>H3-3A<\/jats:italic>\n                    cDNA and an orthotopic xenograft with patient-derived cells. In both models, ASO treatment restored K27 trimethylation of histone H3 proteins and reduced tumor growth, promoted neural stem cell differentiation into astrocytes, neurons, and oligodendrocytes, and increased survival. These results demonstrate the involvement of the H3.3K27M oncohistone in tumor maintenance, confirm the reversibility of the aberrant epigenetic changes it promotes, and provide preclinical proof of concept for DMG antisense therapy.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.add8280","type":"journal-article","created":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T13:58:13Z","timestamp":1681307893000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":36,"title":["Antisense oligonucleotide therapy for H3.3K27M diffuse midline glioma"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6721-3594","authenticated-orcid":true,"given":"Qian","family":"Zhang","sequence":"first","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA."},{"name":"Stony Brook University, Graduate Program in Molecular and Cell Biology, Stony Brook, NY, 11794, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7881-9724","authenticated-orcid":true,"given":"Lucia","family":"Yang","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA."},{"name":"Stony Brook University, Graduate Program in Genetics, Stony Brook, NY, 11794, USA."},{"name":"Medical Scientist Training Program, Stony Brook University School of Medicine, Stony Brook, NY, 11794, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7420-0265","authenticated-orcid":true,"given":"Ying Hsiu","family":"Liu","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9174-8556","authenticated-orcid":true,"given":"John E.","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9024-9501","authenticated-orcid":true,"given":"Adrian R.","family":"Krainer","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.08.008"},{"key":"e_1_3_3_3_2","unstructured":"www.danafarberbostonchildrens.org\/conditions\/brain-tumor\/diffuse-pontine-glioma.aspx."},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1232245"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1255104"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09140-x"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-019-01975-4"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-015-1478-0"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2950"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3855"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.01.014"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-neuro-070918-050501"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-020-0075-7"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.prot077982"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08823-9"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-16-0389"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.11.015"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1941310"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10485"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature21029"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2388-4"},{"key":"e_1_3_3_22_2","first-page":"4382","article-title":"Posttranslational modifications define course of prion strain adaptation and disease phenotype","volume":"130","author":"Makarava N.","year":"2020","unstructured":"N.\u00a0Makarava, J. 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