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Inhibition of the DNA repair enzyme, O\u2076-methylguanine-DNA methyltransferase (MGMT), promotes sensitivity to TMZ, particularly in tumors that repress\n                      <jats:italic>MGMT<\/jats:italic>\n                      mRNA transcription through promoter methylation. Novel strategies to inhibit\n                      <jats:italic>MGMT<\/jats:italic>\n                      are a promising avenue to improve therapeutic outcomes to TMZ. We hypothesized that CRISPR-Cas13-mediated RNA regulatory silencing of\n                      <jats:italic>MGMT<\/jats:italic>\n                      mRNA enhances response of immortalized and primary patient-derived gliomaspheres to TMZ in vitro.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We utilized the Cas13x and Cas13d variants to target\n                      <jats:italic>MGMT<\/jats:italic>\n                      mRNA in the MGMT-expressing LN18 glioma cell line and in two patient-derived gliomasphere lines (GS104, GS081). Cas13-guide RNA ribonucleoproteins were delivered via lipofection, and stable knockdown was achieved using a lentiviral all-in-one system.\n                      <jats:italic>MGMT<\/jats:italic>\n                      mRNA and protein downregulation were assessed by RT-PCR and Western blot, respectively. Cell viability and chemosensitivity to TMZ were evaluated using MTT assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Both Cas13x and Cas13d systems, directed by specific guide CRISPR RNAs, achieved rapid and potent knockdown of\n                      <jats:italic>MGMT<\/jats:italic>\n                      mRNA and protein in all tested cell lines. This downregulation of MGMT expression led to an increase in the cytotoxic effects of TMZ, sensitizing previously resistant glioma cells and patient-derived gliomaspheres to standard chemotherapy. The lentiviral Cas13d system established stable chemosensitization in gliomasphere models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      CRISPR-Cas13-mediated targeting of\n                      <jats:italic>MGMT<\/jats:italic>\n                      mRNA is an effective strategy for overcoming TMZ resistance in in vitro glioblastoma models. This RNA regulatory editing approach offers a proof-of-principle for CRISPR mediated therapeutics in patients with\n                      <jats:italic>MGMT<\/jats:italic>\n                      unmethylated gliomas.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11060-026-05500-y","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T11:16:03Z","timestamp":1773314163000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MGMT downregulation by CRISPR\/Cas13 RNA-guided RNA targeting enhances glioma cell sensitivity to TMZ chemotherapy"],"prefix":"10.1007","volume":"177","author":[{"given":"Terry J.","family":"Prins","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Addison","family":"Fisher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blaine S. 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The Regents of the University of California (T.F.C. employer) has licensed intellectual property co-invented by TFC to Katmai Pharmaceuticals. L.M.L. has equity holdings in ClearPoint Neuro, is on the scientific advisory committee of Northwest Biotherapeutics, and has received research funding from Merck.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"48"}}