Methods and compositions for treating Huntington's disease

1. A method of increasing levels of at least two of PDE10a, DARPP-32, DRD1 and DRD2 in a medium spiny neuron (MSN) of a mouse or human subject, the method comprising administering to the striatum of the subject a genetic repressor comprising a polynucleotide encoding a zinc finger protein DNA-binding protein (ZFP) comprising 3 to 6 zinc finger domains comprising the recognition helix regions in the order shown in a single row of Table 1B, which ZFP binds to a target sequence as shown in Table 2B, wherein the repressor represses transcription of a mutant Huntingtin (Htt) gene, thereby increasing levels of at least two of PDE10a, DARPP-32, DRD1 and DRD2 in the subject at least 30% as compared to a control subject which was not administered the genetic repressor.

2. The method of claim 1 , wherein the PDE10a, DARPP-32, DRD1 and/or DRD2 levels are increased at least 40% or 50% or more relative to the control.

3. The method of claim 1 , wherein the DNA-binding domain is fused to a functional domain.

4. The method of claim 3 , wherein the functional domain is a transcriptional repression domain or a nuclease.

5. The method of claim 1 , wherein the genetic repressor is administered using a viral or non-viral vector.

6. The method of claim 5 , wherein the non-viral vector is an adeno-associated virus (AAV) vector.

7. A method of treating Huntington's Disease in a mouse or human subject with a mutant Htt gene, the method comprising increasing levels of at least two of PDE10a, DARPP-32, DRD1 and DRD2 in a medium spiny neuron (MSN) according to the method of claim 1 .

8. The method of claim 1 , wherein levels of at least three of PDE10a, DARPP-32, DRD1 and DRD2 are increased.

9. The method of claim 8 , wherein levels of PDE10a, DARPP-32, DRD1 and DRD2 are increased.