Extracellular Vesicle–Mediated Delivery of Circular RNA SCMH1 Promotes Functional Recovery in Rodent and Nonhuman Primate Ischemic Stroke Models
Top Cited Papers
- 11 August 2020
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 142 (6), 556-574
- https://doi.org/10.1161/circulationaha.120.045765
Abstract
Background: Stroke is a leading cause of adult disability that can severely compromise the quality of life of patients, yet no effective medication currently exists to accelerate rehabilitation. A variety of circular RNA (circRNA) molecules are known to function in ischemic brain injury. Lentivirus-based expression systems have been widely used in basic studies of circRNAs, but safety issues with such delivery systems have limited exploration of the potential therapeutic roles for circRNAs. Methods: Circular RNA SCMH1 (circSCMH1) was screened from the plasma of patients with acute ischemic stroke by using circRNA microarrays. Engineered rabies virus glycoprotein-circSCMH1-extracellular vesicles were generated to selectively deliver circSCMH1 to the brain. Nissl staining was used to examine infarct size. Behavioral tasks were performed to evaluate motor functions in both rodent and nonhuman primate ischemic stroke models. Golgi staining and immunostaining were used to examine neuroplasticity and glial activation. Proteomic assays and RNA-sequencing data combined with transcriptional profiling were used to identify downstream targets of circSCMH1. Results: CircSCMH1 levels were significantly decreased in the plasma of patients with acute ischemic stroke, offering significant power in predicting stroke outcomes. The decreased levels of circSCMH1 were further confirmed in the plasma and peri-infarct cortex of photothrombotic stroke mice. Beyond demonstrating proof-of-concept for an RNA drug delivery technology, we observed that circSCMH1 treatment improved functional recovery after stroke in both mice and monkeys, and we discovered that circSCMH1 enhanced the neuronal plasticity and inhibited glial activation and peripheral immune cell infiltration. CircSCMH1 binds mechanistically to the transcription factor MeCP2 (methyl-CpG binding protein 2), thereby releasing repression of MeCP2 target gene transcription. Conclusions: Rabies virus glycoprotein-circSCMH1-extracellular vesicles afford protection by promoting functional recovery in the rodent and the nonhuman primate ischemic stroke models. Our study presents a potentially widely applicable nucleotide drug delivery technology and demonstrates the basic mechanism of how circRNAs can be therapeutically exploited to improve poststroke outcomes.This publication has 67 references indexed in Scilit:
- A New Non-Human Primate Model of Photochemically Induced Cerebral InfarctionPLOS ONE, 2013
- Genome-Wide Activity-Dependent MeCP2 Phosphorylation Regulates Nervous System Development and FunctionNeuron, 2011
- Neuroplasticity in the context of motor rehabilitation after strokeNature Reviews Neurology, 2011
- Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after strokeNature, 2010
- ABC/2 for rapid clinical estimate of infarct, perfusion, and mismatch volumesNeurology, 2009
- Mecp2-Null Mice Provide New Neuronal Targets for Rett SyndromePLOS ONE, 2008
- Acute Ischemic Stroke Treatment in 2007Circulation, 2007
- FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null miceHuman Molecular Genetics, 2007
- Effect of Brain-Derived Neurotrophic Factor Treatment and Forced Arm Use on Functional Motor Recovery After Small Cortical IschemiaStroke, 2004
- Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment.Stroke, 1993