Molecular therapy. Nucleic acidsAug 28, 2026

Improved Npc1 mRNA helps fix Niemann-Pick type C1 disease signs in cells and living animals

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 29, 2026

Abstract

A single intravenous injection of Co-Npc1:LNP restored hepatic NPC1 protein levels in a mouse model of Niemann-Pick type C1 disease.

Enhanced NPC1 protein expression and prolonged therapeutic activity were observed using codon-optimized Npc1 mRNA delivered by lipid nanoparticles.
The treatment normalized autophagic flux and improved lipid abnormalities in the Npc1 -/- mouse model.
Markers of liver injury were altered following Co-Npc1:LNP administration.
Transcriptional analysis identified restored pathways related to cholesterol metabolism, lysosomal function, and liver homeostasis.
The mouse liver exhibited a transcriptional shift toward a more Npc1 +/+ state after treatment.

Simplified

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 toward 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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An mRNA treatment restored liver protein and improved disease markers in mice

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Improved Npc1 mRNA helps fix Niemann-Pick type C1 disease signs in cells and living animals

Abstract

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