Rescue of glutaric aciduria type I in mice by liver-directed therapies.
Mercedes BarziCollin G JohnsonTong ChenRamona M RodriguizMadeline HemmingsenTrevor J GonzalezAlan RosalesJames BeasleyCheryl K PeckYunhan MaAshlee R StilesTimothy C WoodRaquel Maeso-DiazAnna Mae DiehlSarah P YoungJeffrey I EverittWilliam C WetselWilliam R LagorBeatrice Bissig-ChoisatAravind AsokanAreeg El-GharbawyKarl-Dimiter BissigPublished in: Science translational medicine (2023)
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 Gcdh gene or we prevented flux through the lysine degradation pathway by CRISPR deletion of the aminoadipate-semialdehyde synthase ( Aass ) gene. Our findings question the current pathophysiological understanding of GA-1 and reveal a targeted therapy for this devastating disorder.
Keyphrases
- pet ct
- gene therapy
- genome wide
- white matter
- mouse model
- resting state
- cerebral ischemia
- copy number
- systematic review
- single cell
- crispr cas
- cell therapy
- amino acid
- multiple sclerosis
- type diabetes
- drug delivery
- gene expression
- dna methylation
- transcription factor
- cancer therapy
- skeletal muscle
- metabolic syndrome
- subarachnoid hemorrhage