CRISPR-Cas9-mediated disruption of the mutant HTT gene in a mouse model of Huntington's disease resulted in a ~50% decrease in neuronal inclusions and significantly improved lifespan.
Does in vivo CRISPR-Cas9-mediated disruption of the mutant HTT gene reduce neuronal inclusions and improve lifespan and motor deficits in the R6/2 mouse model of Huntington's disease?
In vivo CRISPR-Cas9 genome editing to disrupt mutant HTT expression reduces neuronal inclusions and improves lifespan and motor deficits in a mouse model of Huntington's disease.
Huntington's disease (HD) is a currently incurable and, ultimately, fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion within exon 1 of the huntingtin (HTT) gene, which results in the production of a mutant protein that forms inclusions and selectively destroys neurons in the striatum and other adjacent structures. The RNA-guided Cas9 endonuclease from CRISPR-Cas9 systems is a versatile technology for inducing DNA double-strand breaks that can stimulate the introduction of frameshift-inducing mutations and permanently disable mutant gene function. Here, we show that the Cas9 nuclease from Staphylococcus aureus, a small Cas9 ortholog that can be packaged alongside a single guide RNA into a single adeno-associated virus (AAV) vector, can be used to disrupt the expression of the mutant HTT gene in the R6/2 mouse model of HD following its in vivo delivery to the striatum. Specifically, we found that CRISPR-Cas9-mediated disruption of the mutant HTT gene resulted in a ∼50% decrease in neuronal inclusions and significantly improved lifespan and certain motor deficits. These results thus illustrate the potential for CRISPR-Cas9 technology to treat HD and other autosomal dominant neurodegenerative disorders caused by a trinucleotide repeat expansion via in vivo genome editing.
Ekman et al. (Fri,) conducted a other in Huntington's disease. CRISPR-Cas9-mediated disruption of the mutant HTT gene was evaluated on Neuronal inclusions, lifespan, and motor deficits. CRISPR-Cas9-mediated disruption of the mutant HTT gene in a mouse model of Huntington's disease resulted in a ~50% decrease in neuronal inclusions and significantly improved lifespan.