Delivery of Hypoxia-Inducible Heme Oxygenase-1 Gene for Site-Specific Gene Therapy in the Ischemic Stroke Animal Model
- Authors
- Choi, Manbok; Oh, Jungju; Rhim, Taiyoun; Lee, Minhyung
- Issue Date
- Sep-2016
- Publisher
- SPRINGER/PLENUM PUBLISHERS
- Keywords
- gene delivery; heme oxygenase-1; hypoxia-inducible gene; ischemic stroke; site-specific gene therapy
- Citation
- PHARMACEUTICAL RESEARCH, v.33, no.9, pp.2250 - 2258
- Indexed
- SCIE
SCOPUS
- Journal Title
- PHARMACEUTICAL RESEARCH
- Volume
- 33
- Number
- 9
- Start Page
- 2250
- End Page
- 2258
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/5510
- DOI
- 10.1007/s11095-016-1962-9
- ISSN
- 0724-8741
- Abstract
- To reduce side effects due to non-specific expression, the heme oxygenase-1 (HO-1) gene under control of a hypoxia-inducible erythropoietin (Epo) enhancer (pEpo-SV-HO-1) was developed for site-specific gene therapy of ischemic stroke. pEpo-SV-HO-1 was constructed by insertion of the Epo enhancer into pSV-HO-1. Dexamethasone-conjugated polyamidoamine (PAMAM-Dexa) was used as a gene carrier. In vitro transfection assays were performed in the Neuro2A cells. In vivo efficacy of pEpo-SV-HO-1 was evaluated in the transient middle cerebral artery occlusion (MCAO) model. In vitro transfection assay with the PAMAM-Dexa/pEpo-SV-HO-1 complex showed that pEpo-SV-HO-1 had higher HO-1 gene expression than pSV-HO-1 under hypoxia. In addition, pEpo-SV-HO-1 reduced the level of apoptosis more efficiently than pSV-HO-1 in Neuro2A cells under hypoxia. For in vivo evaluation, the PAMAM-Dexa/pEpo-SV-HO-1 complex was injected into the ischemic brain of the transient MCAO model. pEpo-SV-HO-1 increased HO-1 expression and reduced the number of apoptotic cells in the ischemic brain, compared with the pSV-HO-1 injection group. As a result, the infarct volume was more efficiently decreased by pEpo-SV-HO-1 than by pSV-HO-1. pEpo-SV-HO-1 induced HO-1 gene expression and therapeutic effect in the ischemic brain. Therefore, pEpo-SV-HO-1 may be useful for site-specific gene therapy of ischemic stroke.
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