Your browser doesn't support javascript.
loading
Extracellular Vesicle-Mediated Delivery of Circular RNA SCMH1 Promotes Functional Recovery in Rodent and Nonhuman Primate Ischemic Stroke Models.
Yang, Li; Han, Bing; Zhang, Zhiting; Wang, Shuguo; Bai, Ying; Zhang, Yuan; Tang, Ying; Du, Lingli; Xu, Ling; Wu, Fangfang; Zuo, Lei; Chen, Xufeng; Lin, Yu; Liu, Kezhong; Ye, Qingqing; Chen, Biling; Li, Bin; Tang, Tianci; Wang, Yu; Shen, Ling; Wang, Guangtian; Ju, Minzi; Yuan, Mengqin; Jiang, Wei; Zhang, John H; Hu, Gang; Wang, Jianhong; Yao, Honghong.
Afiliación
  • Yang L; Department of Pharmacology, School of Medicine (L.Y., B.H., Y.B., Y.Z., Y.T., F.W., Q.Y., B.C., B.L., T.T., Y.W., L.S., G.W., M.J., H.Y.), Southeast University, Nanjing, China.
  • Han B; Department of Pharmacology, School of Medicine (L.Y., B.H., Y.B., Y.Z., Y.T., F.W., Q.Y., B.C., B.L., T.T., Y.W., L.S., G.W., M.J., H.Y.), Southeast University, Nanjing, China.
  • Zhang Z; National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility) (Z.Z., L.D., L.X., Y.L., K.L., J.W.), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • Wang S; Institutes of Physical Science and Information Technology, Anhui University, Hefei, China (Z.Z., K.L.).
  • Bai Y; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (Z.Z.).
  • Zhang Y; Department of Neurosurgery, First Affiliation Hospital of Kunming Medical University, Kunming, China (S.W.).
  • Tang Y; Department of Pharmacology, School of Medicine (L.Y., B.H., Y.B., Y.Z., Y.T., F.W., Q.Y., B.C., B.L., T.T., Y.W., L.S., G.W., M.J., H.Y.), Southeast University, Nanjing, China.
  • Du L; Department of Pharmacology, School of Medicine (L.Y., B.H., Y.B., Y.Z., Y.T., F.W., Q.Y., B.C., B.L., T.T., Y.W., L.S., G.W., M.J., H.Y.), Southeast University, Nanjing, China.
  • Xu L; Department of Pharmacology, School of Medicine (L.Y., B.H., Y.B., Y.Z., Y.T., F.W., Q.Y., B.C., B.L., T.T., Y.W., L.S., G.W., M.J., H.Y.), Southeast University, Nanjing, China.
  • Wu F; National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility) (Z.Z., L.D., L.X., Y.L., K.L., J.W.), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • Zuo L; National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility) (Z.Z., L.D., L.X., Y.L., K.L., J.W.), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • Chen X; Department of Pharmacology, School of Medicine (L.Y., B.H., Y.B., Y.Z., Y.T., F.W., Q.Y., B.C., B.L., T.T., Y.W., L.S., G.W., M.J., H.Y.), Southeast University, Nanjing, China.
  • Lin Y; Department of Neurology of Affiliated ZhongDa Hospital, Institute of Neuropsychiatry of Southeast University (L.Z.), Southeast University, Nanjing, China.
  • Liu K; Emergency Department, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, China (X.C.).
  • Ye Q; National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility) (Z.Z., L.D., L.X., Y.L., K.L., J.W.), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • Chen B; National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility) (Z.Z., L.D., L.X., Y.L., K.L., J.W.), Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
  • Li B; Department of Pharmacology, School of Medicine (L.Y., B.H., Y.B., Y.Z., Y.T., F.W., Q.Y., B.C., B.L., T.T., Y.W., L.S., G.W., M.J., H.Y.), Southeast University, Nanjing, China.
  • Tang T; Department of Pharmacology, School of Medicine (L.Y., B.H., Y.B., Y.Z., Y.T., F.W., Q.Y., B.C., B.L., T.T., Y.W., L.S., G.W., M.J., H.Y.), Southeast University, Nanjing, China.
  • Wang Y; Department of Pharmacology, School of Medicine (L.Y., B.H., Y.B., Y.Z., Y.T., F.W., Q.Y., B.C., B.L., T.T., Y.W., L.S., G.W., M.J., H.Y.), Southeast University, Nanjing, China.
  • Shen L; Department of Pharmacology, School of Medicine (L.Y., B.H., Y.B., Y.Z., Y.T., F.W., Q.Y., B.C., B.L., T.T., Y.W., L.S., G.W., M.J., H.Y.), Southeast University, Nanjing, China.
  • Wang G; Department of Pharmacology, School of Medicine (L.Y., B.H., Y.B., Y.Z., Y.T., F.W., Q.Y., B.C., B.L., T.T., Y.W., L.S., G.W., M.J., H.Y.), Southeast University, Nanjing, China.
  • Ju M; Department of Pharmacology, School of Medicine (L.Y., B.H., Y.B., Y.Z., Y.T., F.W., Q.Y., B.C., B.L., T.T., Y.W., L.S., G.W., M.J., H.Y.), Southeast University, Nanjing, China.
  • Yuan M; Department of Pharmacology, School of Medicine (L.Y., B.H., Y.B., Y.Z., Y.T., F.W., Q.Y., B.C., B.L., T.T., Y.W., L.S., G.W., M.J., H.Y.), Southeast University, Nanjing, China.
  • Jiang W; Department of Pharmacology, School of Medicine (L.Y., B.H., Y.B., Y.Z., Y.T., F.W., Q.Y., B.C., B.L., T.T., Y.W., L.S., G.W., M.J., H.Y.), Southeast University, Nanjing, China.
  • Zhang JH; College of Automation Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, China (M.Y., W.J.).
  • Hu G; College of Automation Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, China (M.Y., W.J.).
  • Wang J; Institutes of Physical Science and Information Technology, Anhui University, Hefei, China (Z.Z., K.L.).
  • Yao H; Department of Physiology, School of Medicine, Loma Linda University, Loma Linda, CA (J.H.Z.).
Circulation ; 142(6): 556-574, 2020 08 11.
Article en En | MEDLINE | ID: mdl-32441115
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.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Rabia / Virus de la Rabia / Encéfalo / Vacunas Antirrábicas / Lentivirus / ARN Circular / Accidente Cerebrovascular Isquémico Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Circulation Año: 2020 Tipo del documento: Article País de afiliación: China
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Rabia / Virus de la Rabia / Encéfalo / Vacunas Antirrábicas / Lentivirus / ARN Circular / Accidente Cerebrovascular Isquémico Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Circulation Año: 2020 Tipo del documento: Article País de afiliación: China