Lipid Nanoparticle Delivery of siRNA to Silence Neuronal Gene Expression in the Brain
| Autor: | Ravi L. Rungta, Paulo Jc Lin, Jay Nair, Hyun B. Choi, Pieter R. Cullis, Brian A. MacVicar, Muthiah Manoharan, Donovan M. Ashby, Rebecca W.Y. Ko |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
0303 health sciences
Small interfering RNA Gene knockdown biology Protein subunit GRIN1 AMPA receptor Bioinformatics Cell biology 03 medical and health sciences 0302 clinical medicine nervous system In vivo Drug Discovery Gene expression biology.protein Molecular Medicine NMDA receptor Original Article 030217 neurology & neurosurgery 030304 developmental biology |
| Zdroj: | Molecular Therapy. Nucleic Acids |
| ISSN: | 2162-2531 |
| DOI: | 10.1038/mtna.2013.65 |
| Popis: | Manipulation of gene expression in the brain is fundamental for understanding the function of proteins involved in neuronal processes. In this article, we show a method for using small interfering RNA (siRNA) in lipid nanoparticles (LNPs) to efficiently silence neuronal gene expression in cell culture and in the brain in vivo through intracranial injection. We show that neurons accumulate these LNPs in an apolipoprotein E-dependent fashion, resulting in very efficient uptake in cell culture (100%) with little apparent toxicity. In vivo, intracortical or intracerebroventricular (ICV) siRNA-LNP injections resulted in knockdown of target genes either in discrete regions around the injection site or in more widespread areas following ICV injections with no apparent toxicity or immune reactions from the LNPs. Effective targeted knockdown was demonstrated by showing that intracortical delivery of siRNA against GRIN1 (encoding GluN1 subunit of the NMDA receptor (NMDAR)) selectively reduced synaptic NMDAR currents in vivo as compared with synaptic AMPA receptor currents. Therefore, LNP delivery of siRNA rapidly manipulates expression of proteins involved in neuronal processes in vivo, possibly enabling the development of gene therapies for neurological disorders.Molecular Therapy-Nucleic Acids (2013) 2, e136; doi:10.1038/mtna.2013.65; published online 3 December 2013. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|