Targeted gene silencing in the nervous system with CRISPR-Cas13

Jackson E. Powell, Colin K.W. Lim, Ramya Krishnan, Tristan X. McCallister, Christian Saporito-Magriña, Maria A. Zeballos, Garrett D. McPheron, Thomas Gaj

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbereabk2485
JournalScience Advances
Issue number3
StatePublished - Jan 2022

ASJC Scopus subject areas

  • General


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