Journal article
Codon-Optimized Npc1 mRNA corrects Niemann-Pick type C1 disease phenotypes in vitro and in vivo
Molecular therapy. Nucleic acids, Vol.37(3), 103022
09/2026
DOI: 10.1016/j.omtn.2026.103022
PMCID: PMC13521171
PMID: 42662950
Abstract
Niemann-Pick type C1 disease is a lysosomal storage disorder caused by mutations in the NPC1 gene, resulting in the accumulation of unesterified cholesterol in multiple tissues. Despite its severity, therapeutic options remain limited. Using codon-optimized Npc1 mRNA delivered by lipid nanoparticles (Co-Npc1:LNPs), we achieved enhanced NPC1 protein expression and prolonged therapeutic activity in vitro, correcting both primary and secondary disease defects. In an Npc1-/- mouse model, a single intravenous injection of Co-Npc1:LNP restored hepatic NPC1 protein levels, normalized autophagic flux, improved lipid abnormalities, and altered markers of liver injury. To interpret transcriptional changes post-Co-Npc1:LNP administration, we performed bulk RNA sequencing and applied MENTOR, a network-based clustering algorithm, and MENTOR-IA, an unbiased functional annotation tool. We identified transcriptionally restored pathways including cholesterol metabolism, lysosomal and mitochondrial function, and liver homeostasis. Overall, the Npc1-/- mouse liver showed a transcriptional shift towards a more Npc1+/+ state post-Co-Npc1:LNP treatment. Integration of single-nucleus RNA sequencing with bulk transcriptomics further revealed cell-type-specific correction of disease-associated gene expression across disease-relevant hepatic cell types. Together, we report the development and in vivo validation of the first mRNA-based therapeutic for Niemann-Pick type C1 disease.
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In vitro and in vivo treatment with lipid nanoparticles encapsulating Npc1 mRNA corrects primary and secondary Niemann-Pick type C1 disease phenotypes. Treatment of Npc1-/- mice restored protein expression, autophagic flux, and lipid processing in the liver. Sequencing revealed broad, cell type–relevant transcriptional shifts toward a non-disease, Npc1+/+ transcriptional landscape.
Details
- Title: Subtitle
- Codon-Optimized Npc1 mRNA corrects Niemann-Pick type C1 disease phenotypes in vitro and in vivo
- Creators
- Ellen R. Koufer - Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA, USA, 52242Alice Townsend - University of Tennessee at KnoxvilleYoungseo Na - University of MichiganAdele B. Correia - University of MichiganNoah K. Latham - University of Iowa, Medical Genetics and GenomicsKoralege C. Pathmasiri - University of Illinois ChicagoOlga Ilnytska - Rutgers, The State University of New JerseyJudith Storch - Rutgers, The State University of New JerseyKyle A. Sullivan - Oak Ridge National LaboratoryTroy Halseth - University of MichiganThaddeus J. Kunkel - University of MichiganElizabeth S. Phillippi - University of IowaMatthew L. Lieberman - University of IowaStephanie M. Cologna - University of Illinois ChicagoAndrew P. Lieberman - University of MichiganDaniel A. Jacobson - Oak Ridge National LaboratoryAnna S. Schwendeman - University of MichiganMark L. Schultz - Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA, USA, 52242
- Resource Type
- Journal article
- Publication Details
- Molecular therapy. Nucleic acids, Vol.37(3), 103022
- DOI
- 10.1016/j.omtn.2026.103022
- PMID
- 42662950
- PMCID
- PMC13521171
- NLM abbreviation
- Mol Ther Nucleic Acids
- ISSN
- 2162-2531
- eISSN
- 2162-2531
- Publisher
- Elsevier Inc
- Grant note
- Life for Liam and Friends Firefly Fund NIH: R35GM154959, T32 GM 145441, R01 NS122746, DA051908, DA051913, DA054071 Office of Science of the U.S. Department of Energy: DE-AC05-00OR22725 US Department of Energy: DE-AC05-00OR22725 Department of Radiology at The University of Iowa: 1S10OD026835 University of Iowa Vice President for Research Carver College of Medicine
This work was funded by Life for Liam and Friends (to M.L.S.), Firefly Fund (to M.L.S.), NIH (R35GM154959 to M.L.S., T32 GM 145441 to E.R.K.; R01 NS122746 to A.P.L.). This research used resources of the Oak Ridge Leadership Computing Facility at the Oak Ridge National Laboratory, which is supported by the Office of Science of the U.S. Department of Energy under contract no. DE-AC05-00OR22725. Multiplex network methods development was supported by NIH grants DA051908 (DAJ, KAS, AT), DA051913 (DAJ, KAS, AT), and DA054071 (DAJ, KAS, AT). The manuscript was coauthored by UT-Battelle, LLC under Contract No. DE-AC05-00OR22725 with the US Department of Energy. The US Government retains and the publisher, by accepting the article for publication, acknowledges that the US Government retains a nonexclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this manuscript, or allow others to do so, for US Government purposes. The authors would like to acknowledge use of the Small Animal Imaging Core Facility, a core resource supported by the Department of Radiology at The University of Iowa with the IVIS purchased through the S10 award 1S10OD026835. The authors would also like to acknowledge use of the University of Iowa Central Microscopy Research Facility, a core resource supported by the University of Iowa Vice President for Research, and the Carver College of Medicine. Graphical abstract was created in BioRender. Koufer, E. (2026) https://BioRender.com/bghza3k.
- Language
- English
- Electronic publication date
- 07/18/2026
- Date published
- 09/2026
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics
- Record Identifier
- 9985213549502771
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