RNA activation as a precision dosing modality: MTL-CEBPA for controlled enzyme elevation in MPS I-H
File(s)
Published version
Author(s)
Reebye, Vikash
Skourti-Stathaki, Konstantina
Vanezis, Konstantinos
Song, Minsun
Przybilla, Michael J
Type
Journal Article
Abstract
Background: 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.
Methods: 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–IDUA relationships in vitro, in vivo, and in legacy clinical samples from cancer patients.
Results: 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 ∼2-fold, durable increase in bone marrow IDUA mRNA and plasma enzyme activity, sustained for up to 4 weeks. In humanized bone marrow–transplanted 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–derived monocytes, increased CEBPA protein levels correlated with higher IDUA levels (R2 = 0.571). Consistent with this, approximately half of evaluable patients exhibited increased plasma IDUA activity following treatment.
Conclusion: 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’s 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.
Methods: 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–IDUA relationships in vitro, in vivo, and in legacy clinical samples from cancer patients.
Results: 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 ∼2-fold, durable increase in bone marrow IDUA mRNA and plasma enzyme activity, sustained for up to 4 weeks. In humanized bone marrow–transplanted 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–derived monocytes, increased CEBPA protein levels correlated with higher IDUA levels (R2 = 0.571). Consistent with this, approximately half of evaluable patients exhibited increased plasma IDUA activity following treatment.
Conclusion: 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’s 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.
Date Issued
2026-05-07
Date Acceptance
2026-03-27
Citation
Frontiers in Medicine, 2026, 13 (1), pp.1-12
ISSN
2296-858X
Publisher
Frontiers Media S.A.
Start Page
1
End Page
12
Journal / Book Title
Frontiers in Medicine
Volume
13
Issue
1
Copyright Statement
© 2026 Reebye, Skourti-Stathaki, Vanezis, Song, Przybilla, Purdie, Tesone, Pizza, Jarvis, Raulf, Andrikakou, Vasara, Setten, Nicholls, Hegre, Saetrom, Habib, Huang, Farzaneh, Li, Rossi, Tomatsu, Khan, Furness, Wynn, Whitley, Jones and Habib. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
License URL
Publication Status
Published
Article Number
1813362
Date Publish Online
2026-05-07