Faculty Collaboration Database

The nucleotide prodrug CERC-913 improves mtDNA content in primary hepatocytes from DGUOK-deficient rats. J Inherit Metab Dis 2021 Mar;44(2):492-501

Date

12/29/2020

Pubmed ID

33368311

DOI

10.1002/jimd.12354

Scopus ID

2-s2.0-85099334921 (requires institutional sign-in at Scopus site)   5 Citations

Abstract

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.

Author List

Vanden Avond MA, Meng H, Beatka MJ, Helbling DC, Prom MJ, Sutton JL, Slick RA, Dimmock DP, Pertusati F, Serpi M, Pileggi E, Crutcher P, Thomas S, Lawlor MW

Author

Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Caco-2 Cells
DNA Copy Number Variations
DNA, Mitochondrial
Female
Hepatocytes
Humans
Male
Mitochondria
Mitochondrial Diseases
Mutation
Nucleotides
Phosphotransferases (Alcohol Group Acceptor)
Prodrugs
Rats
Rats, Transgenic