Delivery of self-replicating messenger RNA into the brain for the treatment of ischemic stroke
- Authors
- Kim, Minkyung; Oh, Jungju; Lee, Youngki; Lee, Eun-Hye; Ko, Seung Hwan; Jeong, Ji Hoon; Park, Chang Hwan; Lee, Minhyung
- Issue Date
- Oct-2022
- Publisher
- ELSEVIER
- Keywords
- Self -replicating mRNA; Ischemic stroke; Gene delivery; Gene therapy; Ischemia-reperfusion
- Citation
- JOURNAL OF CONTROLLED RELEASE, v.350, pp.471 - 485
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF CONTROLLED RELEASE
- Volume
- 350
- Start Page
- 471
- End Page
- 485
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/172527
- DOI
- 10.1016/j.jconrel.2022.08.049
- ISSN
- 0168-3659
- Abstract
- Ischemic stroke is caused by the occlusion of cerebral arteries. In the ischemic stroke, ischemia-reperfusion injury increases the damage in the brain after reperfusion. In the previous study, heme oxygenase-1 (HO1) mRNA was delivered into the ischemic brain, showing that HO1-mRNA had higher therapeutic effect and less side-effect than HO1-plasmid (pHO1). However, mRNA is degraded faster than plasmid DNA reducing the duration of gene expression. In this study, self-replicating mRNA (Rep-mRNA) was developed using a replicon system from Venezuelan Equine Encephalitis virus to compensate this disadvantage of mRNA delivery. Deoxycholic acid-conjugated polyethylenimine (DA-PEI) was used as a carrier of the mRNAs. The Rep-mRNA/DA-PEI complex had a size of around 90 nm and a zeta-potential of 33 mV. In the in vitro transfection assays, gene expression by the HO1-Rep-mRNA/DA-PEI complex persisted at least 14 days, while that by the HO1-mRNA/DA-PEI complex approached basal level at 3 days after transfection. Therapeutic effects of the HO1-Rep-mRNA/DA-PEI complexes were evaluated in the ischemic stroke animal model. The complexes were injected into the brain stereotaxically. HO1 expression by the HO1-Rep-mRNA/DA-PEI complex persisted at least 7 days after injection, but the pHO1/DA-PEI or HO1-mRNA/DA-PEI complex showed basal level of HO1-expression at 7 days after injection. Due to higher and longer expression of HO1, the apoptosis level and infarct size were decreased by the HO1-Rep-mRNA/DA-PEI complexes, compared with the pHO1/DA-PEI and HO1-mRNA/DA-PEI complex. These results suggest that HO1-Rep-mRNA/DA-PEI complex may have a potential as a long-lasting therapeutic system for the treatment of ischemic stroke.
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