Bezafibrate Enhances AAV Vector-Mediated Genome Editing in Glycogen Storage Disease Type Ia
| Autor: | Lauren R Waskowicz, Andrea M. Seifts, Dwight D. Koeberl, Sarah P. Young, Hye-Ri Kang, Dustin J. Landau |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Agonist zinc-finger nuclease autophagy medicine.medical_specialty G6PC lcsh:QH426-470 medicine.drug_class Genetic enhancement Context (language use) adeno-associated virus Hypoglycemia Biology glycogen storage disease type Ia medicine.disease_cause Article 03 medical and health sciences 0302 clinical medicine Internal medicine Genetics medicine genome editing lcsh:QH573-671 Receptor Molecular Biology Adeno-associated virus bezafibrate Bezafibrate lcsh:Cytology pan-agonist of peroxisome proliferator-activated receptors medicine.disease gene therapy 3. Good health lcsh:Genetics 030104 developmental biology Endocrinology 030220 oncology & carcinogenesis Molecular Medicine medicine.drug |
| Zdroj: | Molecular Therapy: Methods & Clinical Development, Vol 13, Iss, Pp 265-273 (2019) Molecular Therapy. Methods & Clinical Development |
| ISSN: | 2329-0501 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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