Rescue of Glutaric Aciduria Type I in Mice by Liver-Directed Therapies

Authors

Mercedes Barzi
Collin G Johnson
Tong Chen
Ramona M Rodriguiz
Madeline Hemmingsen
Trevor J Gonzalez
Alan Rosales
James Beasley
Cheryl K Peck
Yunhan Ma
Ashlee R Stiles
Timothy C Wood
Raquel Maeso-Diaz
Anna Mae Diehl
Sarah P Young
Jeffrey I Everitt
William C Wetsel
William R Lagor
Beatrice Bissig-Choisat
Aravind Asokan
Areeg El-Gharbawy
Karl-Dimiter Bissig

Publication Date

4-19-2023

Journal

Science Translational Medicine

DOI

10.1126/scitranslmed.adf4086

PMID

37075130

PMCID

PMC10676743

PubMedCentral® Posted Date

11-26-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Glutaryl-CoA Dehydrogenase, Lysine, Mice, Knockout, Amino Acid Metabolism, Inborn Errors, Brain Diseases, Metabolic, Liver, Mice, Animals

Abstract

Glutaric aciduria type I (GA-1) is an inborn error of metabolism with a severe neurological phenotype caused by the deficiency of glutaryl-coenzyme A dehydrogenase (GCDH), the last enzyme of lysine catabolism. Current literature suggests that toxic catabolites in the brain are produced locally and do not cross the blood-brain barrier. In a series of experiments using knockout mice of the lysine catabolic pathway and liver cell transplantation, we uncovered that toxic GA-1 catabolites in the brain originated from the liver. Moreover, the characteristic brain and lethal phenotype of the GA-1 mouse model was rescued by two different liver-directed gene therapy approaches: Using an adeno-associated virus, we replaced the defective

Comments

Associated Data