Huntington’s disease (HD) is an inherited disorder that causes degeneration of brain cells, called neurons, in motor control regions of the brain as well as other areas. Symptoms of the disease, which get progressively worse, include uncontrolled movements (called chorea), abnormal body postures, and changes in behavior, emotion, judgment and cognition.
This neurodegenerative disorder is caused by a polyglutamine repeat in the Huntingtin gene (HTT). Different therapeutic strategies have been explored to treat HD. As the complete loss of the Htt gene in mice lead to embryonic lethality, considerable efforts have been made to develop allele-specific suppression of the expression of mutant versions of the Htt gene (mHtt). Indeed, siRNA and antisense oligonucleotides have shown promising therapeutic effects in mice that express transgenic mHTT but all those strategies relied on single nucleotide polymorphisms specific to each mutant allele.
However an important therapeutic option remained unknown: could a complete depletion of Htt expression in the adult brain be a safe therapy?
To answer this, the authors used the CRISPR-Cas9 technology that can specifically modify a gene locus after the gene editing machinery has been delivered to target cells. The nuclease action around the polyglutamine repeats were specifically targeted to ensure their excision from the mHtt gene. Using this protocol, they managed to permanently suppress the endogenous mHTT expression in the striatum of mHTT-expressing mice. Interestingly, the reduction of mHTT expression in striatal neuronal cells in adult mice did not affect their viability. Additionally, the authors observed a reduction of HTT aggregates in the mice’s brain and a reduction of their motor deficits.
In conclusion, this study suggests that non–allele-specific CRISPR/Cas9-mediated gene editing could be used to efficiently and permanently eliminate polyglutamine expansion–mediated neuronal toxicity in the adult brain.
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