Compositions and Methods for Treating Huntington's Disease and Related Disorders

2:

• A method for reducing the expression of a mutant protein encoded by an allele of a gene associated with a polyglutamine disorder in a cell, said method comprising delivering to the cell a nucleic acid molecule encoding Cas9 and at least one guide RNA,
• wherein said polyglutamine disorder is characterized by an abnormally high number of cytosine-adenine-guanine (CAG) repeats resulting in an extended polyglutamine tract in the encoded for mutant protein.

3:

• The method of claim 1, wherein said polyglutamine disorder is Huntington's disorder and said gene is the huntingtin (HTT) gene.

4:

• The method of claim 1, wherein said method comprises administering to the subject a nucleic acid molecule encoding Cas9, at least one guide RNA, and, optionally at least one donor DNA.

5:

• The method of claim 1, wherein said guide RNA are administered as a nucleic acid molecule encoding said guide RNA.

6:

• The method of claim 5, wherein said nucleic acid molecules are administered in an expression vector.

7:

• The method of claim 6, wherein said expression vector is a viral vector.

8:

• The method of claim 1, wherein at least one guide RNA targets a sequence adjacent to a PAM present on only one allele of the gene.

9:

• The method of claim 8, wherein said PAM is present only on the mutant allele.

10:

• The method of claim 1, wherein two guide RNAs are administered.

11:

• The method of claim 10, wherein at least one of the guide RNA targets a sequence adjacent to a PAM present on only one allele of the gene.

12:

• The method of claim 10, wherein a first guide RNA targets a sequence within the promoter or 5′ untranslated region of the gene and a second guide RNA targets a sequence within the first intron of the gene.

13:

• The method of claim 10, wherein the first guide RNA comprises sgHD1 and the second guide RNA comprises sgHDi3.

14:

• An isolated guide RNA, wherein said guide RNA targets a sequence adjacent to a PAM present on only one allele of a gene associated with a polyglutamine disorder.

15:

• A nucleic acid molecule encoding at least one of the guide RNA of claim 14.

16:

• A vector comprising the nucleic acid molecule of claim 15.

17:

• The vector of claim 16, which is a viral vector.

18:

• The vector of claim 16, further comprising a nucleic acid molecule encoding Cas9.

19:

• A composition comprising at least one nucleic acid molecule of claim 15 or at least one guide RNA of claim 14 and a carrier.