RNA Activation of CEBPA in PBMCs Enhances α-L-Iduronidase Expression A Translational Adjuvant Therapy for MPS I After Bone Marrow Transplantation

Background Hurler syndrome, the most severe form of mucopolysaccharidosis type I (MPS I), is a rare genetic disorder caused by mutations in the IDUA gene, leading to a deficiency of the α-L-iduronidase enzyme. While current treatments offer some benefits, there remains a significant unmet medical need. We have identified a potential new therapeutic approach using MTL-CEBPA, a drug that upregulates the transcription factor CEBPA , which in turn regulates IDUA expression. Results In vitro studies demonstrated significant upregulation of IDUA in various cell lines following MTL-CEBPA treatment. In vivo experiments in both wild-type and MPS I mouse models showed a two-fold increased IDUA expression and enzyme activity for up to four weeks after a single dose. Analysis of archival samples from cancer patients treated with MTL-CEBPA revealed a correlation between increased CEBPA expression and IDUA expression, with approximately half of the patients showing elevated plasma IDUA enzyme activity post-treatment. Conclusions These findings provide proof-of-concept evidence supporting the potential use of MTL-CEBPA as a treatment for MPS I patients. We propose that this therapeutic oligonucleotide approach offers a favourable safety profile, allowing for multiple dosing to maintain elevated IDUA enzyme activity in bone marrow transplanted patients over extended periods, potentially addressing the limitations of current treatments and improving patient outcomes.