Methods for treating Parkinson's disease
The present invention provides methods for treating Parkinson's Disease (PD), e.g., PD associated with a genetic mutation in a glucocerebrosidase (GBA) gene or a leucine rich repeat kinase 2 (LRRK2) gene. The methods comprise administering to the subject a modulator, e.g., an inhibitor, of p53-inducible gene 3 (PIG3).
1. A method of treating Parkinson's Disease (PD) in a human subject in need thereof, the method comprising administering to the subject an inhibitor of human p53-inducible gene 3 (PIG3) (PIG3 inhibitor), wherein the inhibitor inhibits PIG3 by associating with or binding PIG3 mRNA, wherein the inhibitor comprises a nucleic acid selected from the group consisting of an antisense nucleic acid molecule, an siRNA, an shRNA, and a dicer substrate siRNA (DsiRNA), and wherein the subject has an increased expression level of PIG3, thereby treating the Parkinson's disease in the subject.
2. The method of claim 1 , wherein the PD is an idiopathic PD.
3. The method of claim 2 , wherein the PD is associated with a genetic mutation.
4. The method of claim 3 , wherein the genetic mutation is in the glucocerebrosidase (GBA) gene.
5. The method of claim 4 , further comprising the step of:
identifying the subject as having a genetic mutation in the GBA gene.
6. The method of claim 4 , wherein the genetic mutation in the GBA gene is selected from the group consisting of N370S mutation and L444P mutation.
7. The method of claim 3 , wherein the genetic mutation is in the leucine rich repeat kinase 2 (LRRK2) gene.
8. The method of claim 7 , further comprising the step of:
identifying the subject as having a genetic mutation in the LRRK2 gene.
9. The method of claim 8 , wherein the genetic mutation in the LRRK2 gene is selected from the group consisting of G2019S mutation, R1441C mutation, R1441G mutation, R1441H mutation, Y1699C mutation, I2020T mutation and N1437H mutation.
10. The method of claim 9 , wherein the genetic mutation in the LRRK2 gene is the G2019S mutation.
11. The method of claim 1 , wherein administering the PIG3 inhibitor to the subject results in inhibition or in slowing down of PD progression in the subject as measured by UPDRS.
12. A method of reducing neuronal cell death in a human subject afflicted with Parkinson's Disease (PD), comprising administering to the subject an inhibitor of p53-inducible gene 3 (PIG3) (PIG3 inhibitor), wherein the inhibitor inhibits PIG3 by associating with or binding to PIG3 mRNA, wherein the inhibitor comprises a nucleic acid selected from the group consisting of an antisense nucleic acid molecule, an siRNA, an shRNA, and a dicer substrate siRNA (DsiRNA), and wherein the subject has an increased expression level of PIG 3 , thereby treating the Parkinson's disease in the subject.
13. The method of claim 12 , wherein the neuronal death is glucocerebrosidase (GCase)-mediated neuronal cell death and wherein the Parkinson's disease is associated with a genetic mutation in the glucocerebrosidase (GBA) gene.
14. The method of claim 13 , wherein the genetic mutation in the GBA gene is selected from the group consisting of N370S mutation and L444P mutation.
15. A method of treating Parkinson's Disease (PD) in a human subject in need thereof, wherein the Parkinson's Disease is associated with a genetic mutation in the glucocerebrosidase (GBA) gene, the method comprising administering to the subject an inhibitor of human p53-inducible gene 3 (PIG3) (PIG3 inhibitor) in combination with an inhibitor of human glucosylceramide synthase (GCS inhibitor),
wherein the PIG3 inhibitor inhibits PIG3 by associating with or binding to PIG3 mRNA, wherein the inhibitor comprises a nucleic acid selected from the group consisting of an antisense nucleic acid molecule, an siRNA, an shRNA, and a dicer substrate siRNA (DsiRNA),
wherein the GCS inhibitor is selected from the group consisting of GZ/SAR402671 and GZ667161, and wherein the subject has an elevated expression level of PIG3, thereby treating the Parkinson's disease in the subject.
16. The method of claim 15 , wherein administering the PIG3 inhibitor to the subject results in inhibition or in slowing down of PD progression in the subject as measured by UPDRS.