| First Author | Barzi M | Year | 2023 |
| Journal | Sci Transl Med | Volume | 15 |
| Issue | 692 | Pages | eadf4086 |
| PubMed ID | 37075130 | Mgi Jnum | J:353632 |
| Mgi Id | MGI:7488336 | Doi | 10.1126/scitranslmed.adf4086 |
| Citation | Barzi M, et al. (2023) Rescue of glutaric aciduria type I in mice by liver-directed therapies. Sci Transl Med 15(692):eadf4086 |
| abstractText | 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. |
