Academic Journal
Bezafibrate Enhances AAV Vector-Mediated Genome Editing in Glycogen Storage Disease Type Ia
| Title: | Bezafibrate Enhances AAV Vector-Mediated Genome Editing in Glycogen Storage Disease Type Ia |
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| Authors: | Hye-Ri Kang, Lauren Waskowicz, Andrea M. Seifts, Dustin J. Landau, Sarah P. Young, Dwight D. Koeberl |
| Source: | Molecular Therapy: Methods & Clinical Development, Vol 13, Iss , Pp 265-273 (2019) |
| Publisher Information: | Elsevier, 2019. |
| Publication Year: | 2019 |
| Collection: | LCC:Genetics LCC:Cytology |
| Subject Terms: | Genetics, QH426-470, Cytology, QH573-671 |
| More Details: | Glycogen storage disease type Ia (GSD Ia) is a rare inherited disease caused by mutations in the glucose-6-phosphatase (G6Pase) catalytic subunit gene (G6PC). Absence of G6Pase causes life-threatening hypoglycemia and long-term complications because of the accumulations of metabolic intermediates. Bezafibrate, a pan-peroxisome proliferator-activated receptor (PPAR) agonist, was administered in the context of genome editing with a zinc-finger nuclease-containing vector (AAV-ZFN) and a G6Pase donor vector (AAV-RoG6P). Bezafibrate treatment increased survival and decreased liver size (liver/body mass, p < 0.05) in combination with genome editing. Blood glucose has higher (p < 0.05) after 4 h of fasting, and liver glycogen accumulation (p < 0.05) was lower in association with higher G6Pase activity (p < 0.05). Furthermore, bezafibrate-treated mice had increased numbers of G6PC transgenes (p < 0.05) and higher ZFN activity (p < 0.01) in the liver compared with controls. PPAR-α expression was increased and PPAR-γ expression was decreased in bezafibrate-treated mice. Therefore, bezafibrate improved hepatocellular abnormalities and increased the transduction efficiency of AAV vector-mediated genome editing in liver, whereas higher expression of G6Pase corrected molecular signaling in GSD Ia. Taken together, bezafibrate shows promise as a drug for increasing AAV vector-mediated genome editing. Keywords: glycogen storage disease type Ia, adeno-associated virus, bezafibrate, gene therapy, genome editing, zinc-finger nuclease, pan-agonist of peroxisome proliferator-activated receptors, autophagy |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2329-0501 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S2329050119300191; https://doaj.org/toc/2329-0501 |
| DOI: | 10.1016/j.omtm.2019.02.002 |
| Access URL: | https://doaj.org/article/de679cdfd2184c5d826d0048eafe3c3b |
| Accession Number: | edsdoj.679cdfd2184c5d826d0048eafe3c3b |
| Database: | Directory of Open Access Journals |
| ISSN: | 23290501 |
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| DOI: | 10.1016/j.omtm.2019.02.002 |
| Published in: | Molecular Therapy: Methods & Clinical Development |
| Language: | English |