Codon-optimized Npc1 mRNA corrects Niemann-Pick type C1 disease phenotypes in vitro and in vivo

Ellen R. Koufer; Alice Townsend; Youngseo Na; Adele B. Correia; Noah K. Latham; Koralege C. Pathmasiri; Olga Ilnytska; Judith Storch; Kyle A. Sullivan; Troy Halseth; Thaddeus J. Kunkel; Elizabeth S. Phillippi; Matthew L. Lieberman; Stephanie M. Cologna; Andrew P. Lieberman; Daniel A. Jacobson; Anna S. Schwendeman; Mark L. Schultz

doi:10.1016/j.omtn.2026.103022

Codon-optimized Npc1 mRNA corrects Niemann-Pick type C1 disease phenotypes in vitro and in vivo

Ellen R. Koufer
, Alice Townsend
, Youngseo Na
, Adele B. Correia
, Noah K. Latham
, Koralege C. Pathmasiri
, Olga Ilnytska
, Judith Storch
, Kyle A. Sullivan
, Troy Halseth
, Thaddeus J. Kunkel
, Elizabeth S. Phillippi
, Matthew L. Lieberman
, Stephanie M. Cologna
, Andrew P. Lieberman
, Daniel A. Jacobson
, Anna S. Schwendeman
, Mark L. Schultz

Computational Systems Biology

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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 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.

Original language	English
Article number	103022
Journal	Molecular Therapy Nucleic Acids
Volume	37
Issue number	3
DOIs	https://doi.org/10.1016/j.omtn.2026.103022
State	Published - Sep 8 2026

Funding

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 .

Keywords

MT: RNA/DNA editing
NPC1
Niemann-Pick type C1
Niemann-Pick type C1 liver
lipid nanoparticle
lysosomal storage disorder
mRNA therapy

Access to Document

10.1016/j.omtn.2026.103022

Cite this

Koufer, E. R., Townsend, A., Na, Y., Correia, A. B., Latham, N. K., Pathmasiri, K. C., Ilnytska, O., Storch, J., Sullivan, K. A., Halseth, T., Kunkel, T. J., Phillippi, E. S., Lieberman, M. L., Cologna, S. M., Lieberman, A. P., Jacobson, D. A., Schwendeman, A. S., & Schultz, M. L. (2026). Codon-optimized Npc1 mRNA corrects Niemann-Pick type C1 disease phenotypes in vitro and in vivo. Molecular Therapy Nucleic Acids, 37(3), Article 103022. https://doi.org/10.1016/j.omtn.2026.103022

@article{e3c8087143bb437496b0235578af5d81,

title = "Codon-optimized Npc1 mRNA corrects Niemann-Pick type C1 disease phenotypes in vitro and in vivo",

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 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.",

keywords = "MT: RNA/DNA editing, NPC1, Niemann-Pick type C1, Niemann-Pick type C1 liver, lipid nanoparticle, lysosomal storage disorder, mRNA therapy",

author = "Koufer, \{Ellen R.\} and Alice Townsend and Youngseo Na and Correia, \{Adele B.\} and Latham, \{Noah K.\} and Pathmasiri, \{Koralege C.\} and Olga Ilnytska and Judith Storch and Sullivan, \{Kyle A.\} and Troy Halseth and Kunkel, \{Thaddeus J.\} and Phillippi, \{Elizabeth S.\} and Lieberman, \{Matthew L.\} and Cologna, \{Stephanie M.\} and Lieberman, \{Andrew P.\} and Jacobson, \{Daniel A.\} and Schwendeman, \{Anna S.\} and Schultz, \{Mark L.\}",

note = "Publisher Copyright: {\textcopyright} 2026 The Authors.",

year = "2026",

month = sep,

day = "8",

doi = "10.1016/j.omtn.2026.103022",

language = "English",

volume = "37",

journal = "Molecular Therapy Nucleic Acids",

issn = "2162-2531",

number = "3",

}

Koufer, ER, Townsend, A, Na, Y, Correia, AB, Latham, NK, Pathmasiri, KC, Ilnytska, O, Storch, J, Sullivan, KA, Halseth, T, Kunkel, TJ, Phillippi, ES, Lieberman, ML, Cologna, SM, Lieberman, AP, Jacobson, DA, Schwendeman, AS & Schultz, ML 2026, 'Codon-optimized Npc1 mRNA corrects Niemann-Pick type C1 disease phenotypes in vitro and in vivo', Molecular Therapy Nucleic Acids, vol. 37, no. 3, 103022. https://doi.org/10.1016/j.omtn.2026.103022

TY - JOUR

T1 - Codon-optimized Npc1 mRNA corrects Niemann-Pick type C1 disease phenotypes in vitro and in vivo

AU - Koufer, Ellen R.

AU - Townsend, Alice

AU - Na, Youngseo

AU - Correia, Adele B.

AU - Latham, Noah K.

AU - Pathmasiri, Koralege C.

AU - Ilnytska, Olga

AU - Storch, Judith

AU - Sullivan, Kyle A.

AU - Halseth, Troy

AU - Kunkel, Thaddeus J.

AU - Phillippi, Elizabeth S.

AU - Lieberman, Matthew L.

AU - Cologna, Stephanie M.

AU - Lieberman, Andrew P.

AU - Jacobson, Daniel A.

AU - Schwendeman, Anna S.

AU - Schultz, Mark L.

PY - 2026/9/8

Y1 - 2026/9/8

N2 - 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.

AB - 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.

KW - MT: RNA/DNA editing

KW - NPC1

KW - Niemann-Pick type C1

KW - Niemann-Pick type C1 liver

KW - lipid nanoparticle

KW - lysosomal storage disorder

KW - mRNA therapy

UR - https://www.scopus.com/pages/publications/105047711957

U2 - 10.1016/j.omtn.2026.103022

DO - 10.1016/j.omtn.2026.103022

M3 - Article

AN - SCOPUS:105047711957

SN - 2162-2531

VL - 37

JO - Molecular Therapy Nucleic Acids

JF - Molecular Therapy Nucleic Acids

IS - 3

M1 - 103022

ER -

Codon-optimized Npc1 mRNA corrects Niemann-Pick type C1 disease phenotypes in vitro and in vivo

Abstract

Funding

Keywords

Access to Document

Other files and links

Fingerprint

Cite this