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

Autor: Vanden Avond MA; Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Meng H; Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Beatka MJ; Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Helbling DC; Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Prom MJ; Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Sutton JL; Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Slick RA; Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Dimmock DP; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, California, USA., Pertusati F; School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK., Serpi M; School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK., Pileggi E; School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK., Crutcher P; Discovery R&D, Cerecor Inc., Rockville, Maryland, USA., Thomas S; Discovery R&D, Cerecor Inc., Rockville, Maryland, USA., Lawlor MW; Department of Pathology and Laboratory Medicine and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Jazyk: angličtina
Zdroj: Journal of inherited metabolic disease [J Inherit Metab Dis] 2021 Mar; Vol. 44 (2), pp. 492-501. Date of Electronic Publication: 2021 Jan 15.
DOI: 10.1002/jimd.12354
Abstrakt: 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.
(© 2020 SSIEM.)
Databáze: MEDLINE
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