Back to Search
Start Over
mRNA Therapy Improves Metabolic and Behavioral Abnormalities in a Murine Model of Citrin Deficiency.
- Source :
-
Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2019 Jul 03; Vol. 27 (7), pp. 1242-1251. Date of Electronic Publication: 2019 Apr 23. - Publication Year :
- 2019
-
Abstract
- Citrin deficiency is an autosomal recessive disorder caused by loss-of-function mutations in SLC25A13, encoding the liver-specific mitochondrial aspartate/glutamate transporter. It has a broad spectrum of clinical phenotypes, including life-threatening neurological complications. Conventional protein replacement therapy is not an option for these patients because of drug delivery hurdles, and current gene therapy approaches (e.g., AAV) have been hampered by immunogenicity and genotoxicity. Although dietary approaches have shown some benefits in managing citrin deficiency, the only curative treatment option for these patients is liver transplantation, which is high-risk and associated with long-term complications because of chronic immunosuppression. To develop a new class of therapy for citrin deficiency, codon-optimized mRNA encoding human citrin (hCitrin) was encapsulated in lipid nanoparticles (LNPs). We demonstrate the efficacy of hCitrin-mRNA-LNP therapy in cultured human cells and in a murine model of citrin deficiency that resembles the human condition. Of note, intravenous (i.v.) administration of the hCitrin-mRNA resulted in a significant reduction in (1) hepatic citrulline and blood ammonia levels following oral sucrose challenge and (2) sucrose aversion, hallmarks of hCitrin deficiency. In conclusion, mRNA-LNP therapy could have a significant therapeutic effect on the treatment of citrin deficiency and other mitochondrial enzymopathies with limited treatment options.<br /> (Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Behavior, Animal drug effects
Disease Models, Animal
Gene Knockout Techniques
Glucosephosphate Dehydrogenase genetics
HeLa Cells
Hep G2 Cells
Humans
Lipids chemistry
Loss of Function Mutation
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria metabolism
Nanoparticles chemistry
Open Reading Frames genetics
RNA, Messenger chemical synthesis
RNA, Messenger chemistry
RNA, Messenger genetics
Transfection
Treatment Outcome
Citrullinemia drug therapy
Citrullinemia metabolism
Drug Delivery Systems methods
Genetic Therapy methods
Mitochondrial Membrane Transport Proteins genetics
Mitochondrial Membrane Transport Proteins metabolism
RNA, Messenger therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1525-0024
- Volume :
- 27
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 31056400
- Full Text :
- https://doi.org/10.1016/j.ymthe.2019.04.017