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The nucleotide prodrug CERC‐913 improves mtDNA content in primary hepatocytes from DGUOK‐deficient rats

Vanden Avond, Mark A., Meng, Hui, Beatka, Margaret J., Helbling, Daniel C., Prom, Mariah J., Sutton, Jessica L., Slick, Rebecca A., Dimmock, David P., Pertusati, Fabrizio ORCID:, Serpi, Michaela ORCID:, Pileggi, Elisa, Crutcher, Patrick, Thomas, Stephen and Lawlor, Michael W. 2021. The nucleotide prodrug CERC‐913 improves mtDNA content in primary hepatocytes from DGUOK‐deficient rats. Journal of Inherited Metabolic Disease 44 (2) , pp. 492-501. 10.1002/jimd.12354

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Loss‐of‐function mutations in the deoxyguanosine kinase (DGUOK) gene result in a mitochondrial DNA (mtDNA) depletion syndrome. DGUOK plays an important role in converting deoxyribonucleosides to deoxyribonucleoside monophosphates via the salvage pathway for mtDNA synthesis. DGUOK deficiency manifests predominantly in the liver; the most common cause of death is liver failure within the first year of life and no therapeutic options are currently available. in vitro supplementation with deoxyguanosine or deoxyguanosine monophosphate (dGMP) were reported to rescue mtDNA depletion in DGUOK‐deficient, patient‐derived fibroblasts and myoblasts. CERC‐913, a novel ProTide prodrug of dGMP, was designed to bypass defective DGUOK while improving permeability and stability relative to nucleoside monophosphates. To evaluate CERC‐913 for its ability to rescue mtDNA depletion, we developed a primary hepatocyte culture model using liver tissue from DGUOK‐deficient rats. DGUOK knockout rat hepatocyte cultures exhibit severely reduced mtDNA copy number (~10%) relative to wild type by qPCR and mtDNA content remains stable for up to 8 days in culture. CERC‐913 increased mtDNA content in DGUOK‐deficient hepatocytes up to 2.4‐fold after 4 days of treatment in a dose‐dependent fashion, which was significantly more effective than dGMP at similar concentrations. These early results suggest primary hepatocyte culture is a useful model for the study of mtDNA depletion syndromes and that CERC‐913 treatment can improve mtDNA content in this model.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Springer Verlag (Germany)
ISSN: 0141-8955
Date of First Compliant Deposit: 21 January 2021
Date of Acceptance: 22 December 2020
Last Modified: 07 Nov 2023 20:13

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