Repurposing the HMG-CoA reductase inhibitor atorvastatin for SRD5A3-congenital disorder of glycosylation.
12 affiliations
- 1Department of Neuroscience, Université de Montréal, Montréal, QC, Canada.
- 2Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.
- 3Modelis Inc, Montréal, QC, Canada.
- 4Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
- 5Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
- 6Perlara PBC, Vancouver, WA, USA.
- 7Department of Biophysics, University of Pécs, Medical School, Pécs, Hungary.
- 8Department of Genomics and Genetic Sciences, Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA.
- 9Manipal Academy of Higher Education, Manipal, India.
- 10Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
- 11Perlara PBC, Vancouver, WA, USA. [email protected].
- 12Sappani Foundation, Brampton, ON, Canada. [email protected].
Abstract
Background
Steroid 5 alpha-reductase 3-related congenital disorder of glycosylation (SRD5A3-CDG) is a rare inherited disease characterized by neurological dysfunction, including ataxia, as well as developmental and visual impairments, with no approved treatments. The disease is caused by defects in dolichol biosynthesis, a pathway essential for protein glycosylation. However, the lack of suitable in vivo models has limited both mechanistic insight and therapeutic development.Methods
We generated a Caenorhabditis elegans model carrying a patient-relevant loss-of-function mutation and performed a motility-based phenotypic drug repurposing screen to identify compounds that improve disease-relevant phenotypes. Lead compounds were evaluated in behavioral, neuronal, and metabolomic assays in worms and in fibroblasts from four individuals with SRD5A3-CDG.Results
Here we show that SRD5A3-deficient worms exhibit developmental delay, neuronal dysfunction, and metabolic alterations consistent with dysregulation of the mevalonate pathway. The screen identifies multiple classes of compounds that improve motility, including the cholesterol-lowering drug atorvastatin. Atorvastatin improves multiple disease-relevant phenotypes in the worm model. In patient-derived fibroblasts, treatment partially restores the balance between polyprenol and dolichol, which is disrupted in SRD5A3-CDG.Conclusions
These findings establish an in vivo model of SRD5A3-CDG and identify modulation of the mevalonate pathway as a potential therapeutic strategy. The results support further investigation of atorvastatin as a repurposed treatment and demonstrate an approach for combining model organism screening with human cell validation to accelerate rare disease drug discovery.
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BibTeX
@article{daghar2026repurposing,
title = {{Repurposing the HMG-CoA reductase inhibitor atorvastatin for SRD5A3-congenital disorder of glycosylation.}},
author = {Hiba Daghar and Seul Kee Byeon and Claudia Maios and Jennifer Poon and James Doyle and Wasantha Ranatunga and Éric Samarut and Ethan O Perlstein and Eva Morava and Akhilesh Pandey and J Alex Parker and Kristin A Kantautas},
journal = {Communications medicine},
year = {2026},
month = jul,
doi = {10.1038/s43856-026-01791-4},
url = {https://europepmc.org/article/MED/42839006},
note = {CC BY},
}
RIS
TY - JOUR
TI - Repurposing the HMG-CoA reductase inhibitor atorvastatin for SRD5A3-congenital disorder of glycosylation.
AU - Hiba Daghar
AU - Seul Kee Byeon
AU - Claudia Maios
AU - Jennifer Poon
AU - James Doyle
AU - Wasantha Ranatunga
AU - Éric Samarut
AU - Ethan O Perlstein
AU - Eva Morava
AU - Akhilesh Pandey
AU - J Alex Parker
AU - Kristin A Kantautas
PY - 2026
DA - 2026/07/29
JO - Communications medicine
DO - 10.1038/s43856-026-01791-4
UR - https://europepmc.org/article/MED/42839006
AB - Background Steroid 5 alpha-reductase 3-related congenital disorder of glycosylation (SRD5A3-CDG) is a rare inherited disease characterized by neurological dysfunction, including ataxia, as well as developmental and visual impairments, with no approved treatments. The disease is caused by defects in dolichol biosynthesis, a pathway essential for protein glycosylation. However, the lack of suitable in vivo models has limited both mechanistic insight and therapeutic development.Methods We generated a Caenorhabditis elegans model carrying a patient-relevant loss-of-function mutation and performed a motility-based phenotypic drug repurposing screen to identify compounds that improve disease-relevant phenotypes. Lead compounds were evaluated in behavioral, neuronal, and metabolomic assays in worms and in fibroblasts from four individuals with SRD5A3-CDG.Results Here we show that SRD5A3-deficient worms exhibit developmental delay, neuronal dysfunction, and metabolic alterations consistent with dysregulation of the mevalonate pathway. The screen identifies multiple classes of compounds that improve motility, including the cholesterol-lowering drug atorvastatin. Atorvastatin improves multiple disease-relevant phenotypes in the worm model. In patient-derived fibroblasts, treatment partially restores the balance between polyprenol and dolichol, which is disrupted in SRD5A3-CDG.Conclusions These findings establish an in vivo model of SRD5A3-CDG and identify modulation of the mevalonate pathway as a potential therapeutic strategy. The results support further investigation of atorvastatin as a repurposed treatment and demonstrate an approach for combining model organism screening with human cell validation to accelerate rare disease drug discovery.
SN - 2730-664X
ER -