{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T05:13:53Z","timestamp":1778130833233,"version":"3.51.4"},"reference-count":18,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Gene therapy and hematopoietic stem cell transplantation (HSCT) have transformed outcomes for severe mucopolysaccharidosis type I (MPS I-H), yet a critical unmet need remains. Children with MPS I-H frequently experience progressive skeletal, cardiac, and other complications despite timely HSCT, largely because enzyme activity cannot be safely and precisely titrated over time. Irreversible genetic modification via integrating vectors offers supra-physiological enzyme levels but carries long-term safety and re-dosing liabilities in patients treated early in life.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated RNA activation (RNAa) as a precision dosing strategy to enhance endogenous IDUA expression without permanent genome alteration. Using MTL-CEBPA, a small activating RNA that upregulates CEBPA transcription factor, we characterized CEBPA\u2013IDUA relationships\n                      <jats:italic>in vitro<\/jats:italic>\n                      ,\n                      <jats:italic>in vivo<\/jats:italic>\n                      , and in legacy clinical samples from cancer patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CCAAT enhancer binding protein alpha activation consistently increased IDUA mRNA across A549, IMR90, and mesenchymal stem cells. In wild-type mice, two intravenous MTL-CEBPA doses produced a \u223c2-fold, durable increase in bone marrow IDUA mRNA and plasma enzyme activity, sustained for up to 4 weeks. In humanized bone marrow\u2013transplanted MPS I-H mice, repeated dosing with MTL-CEBPA led to an approximately 2-fold increase in circulating IDUA activity compared with controls over the 3-weeks treatment period. The largest apparent separation from controls was observed in the homozygous cohort, although these genotype-specific differences should be interpreted cautiously given the limited subgroup sizes. In cancer patient\u2013derived monocytes, increased CEBPA protein levels correlated with higher IDUA levels (R\n                      <jats:sup>2<\/jats:sup>\n                      = 0.571). Consistent with this, approximately half of evaluable patients exhibited increased plasma IDUA activity following treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These translational data demonstrate that MTL-CEBPA delivers controlled, reversible enhancement of IDUA in the context of HSCT, providing robust pharmacodynamic proof-of-concept rather than definitive evidence of durable efficacy. By enabling titratable enzyme elevation without integrating vectors, RNAa therapeutics address a key unmet need in Hurler syndrome: safe fine-tuning of residual enzyme activity over a patient\u2019s lifetime. With scalable, cost-effective oligonucleotide manufacturing, MTL-CEBPA and related RNAa therapeutics represent a clinically relevant adjuvant strategy for HSCT-treated MPS I-H, with potential for other enzyme deficiency disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1813362","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T04:51:48Z","timestamp":1778129508000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["RNA activation as a precision dosing modality: MTL-CEBPA for controlled enzyme elevation in MPS I-H"],"prefix":"10.3389","volume":"13","author":[{"given":"Vikash","family":"Reebye","sequence":"first","affiliation":[{"name":"Department of Surgery and Cancer, Imperial College London","place":["London, United Kingdom"]},{"name":"MiNA Therapeutics Limited","place":["London, United Kingdom"]},{"name":"Dawn Therapeutics Limited","place":["London, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantina","family":"Skourti-Stathaki","sequence":"additional","affiliation":[{"name":"MiNA Therapeutics Limited","place":["London, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantinos","family":"Vanezis","sequence":"additional","affiliation":[{"name":"MiNA Therapeutics Limited","place":["London, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minsun","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Molecular & Cellular Biology, Beckman Research Institute of City of Hope","place":["Duarte, CA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Przybilla","sequence":"additional","affiliation":[{"name":"Division of Pediatric Blood and Bone Marrow Transplantation","place":["Minneapolis, MN, United 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Limited","place":["London, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pinelopi","family":"Andrikakou","sequence":"additional","affiliation":[{"name":"Department of Surgery and Cancer, Imperial College London","place":["London, United Kingdom"]},{"name":"MiNA Therapeutics Limited","place":["London, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenni","family":"Vasara","sequence":"additional","affiliation":[{"name":"MiNA Therapeutics Limited","place":["London, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Setten","sequence":"additional","affiliation":[{"name":"Department of Molecular & Cellular Biology, Beckman Research Institute of City of Hope","place":["Duarte, CA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanna","family":"Nicholls","sequence":"additional","affiliation":[{"name":"Department of Surgery and Cancer, Imperial College London","place":["London, United Kingdom"]},{"name":"MiNA Therapeutics Limited","place":["London, United Kingdom"]},{"name":"Dawn Therapeutics Limited","place":["London, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siv Anita","family":"Hegre","sequence":"additional","affiliation":[{"name":"Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology","place":["Trondheim, Norway"]},{"name":"Department of Computer and Information Science, Norwegian University of Science and Technology","place":["Trondheim, Norway"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P\u00e4l","family":"S\u00e6trom","sequence":"additional","affiliation":[{"name":"Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology","place":["Trondheim, Norway"]},{"name":"Department of Computer and Information Science, Norwegian University of Science and Technology","place":["Trondheim, Norway"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Habib","sequence":"additional","affiliation":[{"name":"MiNA Therapeutics Limited","place":["London, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai-Wen","family":"Huang","sequence":"additional","affiliation":[{"name":"National Taiwan University Hospital","place":["Taipei, Taiwan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farzin","family":"Farzaneh","sequence":"additional","affiliation":[{"name":"The Rayne Institute, King\u2019s College London","place":["London, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haitang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Molecular & Cellular Biology, Beckman Research Institute of City of Hope","place":["Duarte, CA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John J.","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Molecular & Cellular Biology, Beckman Research Institute of City of Hope","place":["Duarte, CA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shunji","family":"Tomatsu","sequence":"additional","affiliation":[{"name":"Skeletal Dysplasia Research Laboratory, Nemours\/Alfred I DuPont Hospital for Children","place":["Wilmington, DE, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaukat","family":"Khan","sequence":"additional","affiliation":[{"name":"Skeletal Dysplasia Research Laboratory, Nemours\/Alfred I DuPont Hospital for Children","place":["Wilmington, DE, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Furness","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, St Mary\u2019s Hospital, Manchester University NHS Foundation Trust","place":["Manchester, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Wynn","sequence":"additional","affiliation":[{"name":"Department of Pediatric Bone Marrow Transplantation, Manchester University NHS Foundation Trust","place":["Manchester, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chester B.","family":"Whitley","sequence":"additional","affiliation":[{"name":"Division of Pediatric Blood and Bone Marrow Transplantation","place":["Minneapolis, MN, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon A.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Pediatric Bone Marrow Transplantation, Manchester University NHS Foundation Trust","place":["Manchester, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nagy A.","family":"Habib","sequence":"additional","affiliation":[{"name":"Department of Surgery and Cancer, Imperial College 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