Progressive liver disease and dysregulated glycogen metabolism in murine GSD IX γ2 models human disease.

Autor: Gibson RA; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA; Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA., Jeck WR; Department of Pathology, Duke University Medical Center, Durham, NC, USA., Koch RL; Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA., Mehta A; Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA., Choi SJ; Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA., Sriraman Y; Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA., Bali D; Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA., Young S; Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA., Asokan A; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA; Department of Surgery, Duke University Medical Center, Durham, NC, USA., Lim JA; Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA., Kishnani PS; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA; Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA. Electronic address: priya.kishnani@duke.edu.
Jazyk: angličtina
Zdroj: Molecular genetics and metabolism [Mol Genet Metab] 2024 Dec; Vol. 143 (4), pp. 108597. Date of Electronic Publication: 2024 Oct 28.
DOI: 10.1016/j.ymgme.2024.108597
Abstrakt: Hepatic glycogen storage disease type IX γ2 (GSD IX γ2) is a severe, liver-specific subtype of GSD IX. While all patients with hepatic GSD IX present with similar symptoms, over 95 % of patients with GSD IX γ2 progress to liver fibrosis and cirrhosis. Despite disease severity, the long-term natural history of GSD IX γ2 liver disease progression is not known. Our lab previously characterized the Phkg2 -/- mouse model at 3 months of age, demonstrating that the mouse recapitulates the early liver disease phenotype of GSD IX γ2. To understand how liver disease progresses in GSD IX γ2, we characterized the mouse model through 24 months of age. Our study showed for the first time that GSD IX γ2 mice develop liver fibrosis that progresses to cirrhosis. Importantly, we observed that the progression of liver fibrosis is associated with an initial elevation and subsequent decrease of key GSD biomarkers - the latter being a finding that is often considered to be an improvement of disease in patients. In recognition of the unique liver fibrosis pattern and to support future therapeutic investigations using this model, we developed a novel scoring system for GSD IX γ2 mouse liver pathology. Lastly, this work introduces evidence of a dysregulated glycogen metabolism pathway which can serve as an endpoint for future therapeutic evaluation. As we await longitudinal clinical natural history data, these findings greatly expand our understanding of liver disease manifestations in GSD IX γ2 and have notable clinical applications.
Competing Interests: Declaration of competing interest RG, AA, JL, and PSK have patents pending. PSK has received research/grant support from Kriya Therapeutics. AA is a cofounder and Board Director at TorqueBio and serves as advisor to Atsena Therapeutics, Ring Therapeutics, Ginkgo Bioworks and Mammoth Biosciences.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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