Use of CRISPR/Cas9 to treat Huntington disease Summary A variety of neurological diseases are caused by the mutations in the disease genes that result in gain of toxicity in the brain. Lowering or blocking the expression of mutant genes is considered an effective therapeutic strategy for the treatment of these neurological disorders. In Huntington disease, the CAG repeat expansion in exon1 of the huntingtin gene leads to selective neurodegeneration and progressive neurological symptoms, which are incurable with the current therapies. We will use a newly developed technology, CRISPR/Cas9, to eliminate the expression of mutant huntingtin in Huntington disease mice. Our preliminary studies have shown the promising effect of CRISPR/Cas9 to alleviate the neurotoxicity and neurological symptoms in Huntington disease mice. However, the long-term effects of CRISPR/Cas9 and the safety issue of this new technology remain to be investigated. The current application will examine the gene targeting efficiency of modified Cas9 in the adult mouse brains in phase 1 studies. The phase 2 studies will rigorously examine the long-term effects of removing mutant huntingtin in Huntington disease mice and potential side effects caused by CRISPR/Cas9. Given the increasing demand to use CRISPR/Cas9 to remove mutant genes in the brain to treat a variety of neurological disorders, our studies will have broad implications for the future clinic use of CRISPR/Cas9 to ameliorate neurological symptoms in brain diseases.