Targeted gene silencing in the nervous system with CRISPR-Cas13.

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Abstrakt

Tytuł:: Targeted gene silencing in the nervous system with CRISPR-Cas13.
Autorzy:: Powell JE; Department of Bioengineering, University of Illinois, Urbana, IL 61801, USA.
Lim CKW; Department of Bioengineering, University of Illinois, Urbana, IL 61801, USA.
Krishnan R; Department of Bioengineering, University of Illinois, Urbana, IL 61801, USA.
McCallister TX; Department of Bioengineering, University of Illinois, Urbana, IL 61801, USA.
Saporito-Magriña C; Department of Bioengineering, University of Illinois, Urbana, IL 61801, USA.
Zeballos MA; Department of Bioengineering, University of Illinois, Urbana, IL 61801, USA.
McPheron GD; Department of Bioengineering, University of Illinois, Urbana, IL 61801, USA.
Gaj T; Department of Bioengineering, University of Illinois, Urbana, IL 61801, USA.; Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801, USA.
Źródło:: Science advances [Sci Adv] 2022 Jan 21; Vol. 8 (3), pp. eabk2485. Date of Electronic Publication: 2022 Jan 19.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]-
MeSH Terms:: Amyotrophic Lateral Sclerosis*/genetics
CRISPR-Cas Systems*
Animals ; Gene Silencing ; Mammals ; Mice ; Spinal Cord ; Superoxide Dismutase ; Superoxide Dismutase-1/genetics
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Grant Information:: R01 GM141296 United States GM NIGMS NIH HHS; T32 EB019944 United States EB NIBIB NIH HHS
Substance Nomenclature:: EC 1.15.1.1 (Superoxide Dismutase)
EC 1.15.1.1 (Superoxide Dismutase-1)
Entry Date(s):: Date Created: 20220119 Date Completed: 20220419 Latest Revision: 20240214
Update Code:: 20240214
PubMed Central ID:: PMC8769545
DOI:: 10.1126/sciadv.abk2485
PMID:: 35044815
: Czasopismo naukowe

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Cas13 nucleases are a class of programmable RNA-targeting CRISPR effector proteins that are capable of silencing target gene expression in mammalian cells. Here, we demonstrate that RfxCas13d, a Cas13 ortholog with favorable characteristics to other family members, can be delivered to the mouse spinal cord and brain to silence neurodegeneration-associated genes. Intrathecally delivering an adeno-associated virus vector encoding an RfxCas13d variant programmed to target superoxide dismutase 1 (SOD1), a protein whose mutation can cause amyotrophic lateral sclerosis, reduced SOD1 mRNA and protein in the spinal cord by >50% and improved outcomes in a mouse model of the disorder. We further show that intrastriatally delivering an RfxCas13d variant programmed to target huntingtin (HTT), a protein whose mutation is causative for Huntington’s disease, led to a ~50% reduction in HTT protein in the mouse brain. Our results establish RfxCas13d as a versatile platform for knocking down gene expression in the nervous system.

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