Methods for treating parkinson's disease

Abstract

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 subject in need thereof, the method comprising administering to the subject an inhibitor of p53-inducible gene 3 (PIG3) (PIG3 inhibitor), wherein the inhibitor inhibits PIG3 by associating or binding to PIG3 protein, wherein the inhibitor comprises a peptide or a polypeptide, 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 or wherein the genetic mutation is in the leucine rich repeat kinase 2 (LRRK2) gene. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 4 , comprising the steps of:
 identifying the subject as having a genetic mutation in the GBA gene or as having a genetic mutation in the LRRK2 gene; and   administering to the subject of the PIG3 inhibitor, thereby treating the Parkinson's disease in the subject.   
     
     
         7 . (canceled) 
     
     
         8 . A method of reducing or preventing neuronal cell death in a 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 or binding to PIG3 protein, wherein the inhibitor comprises a peptide or a polypeptide, and wherein the subject has an increased expression level of PIG3, thereby reducing or preventing neuronal cell death in the subject. 
     
     
         9 . The method of  claim 8 , 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 or wherein the neuronal death is leucine rich repeat kinase 2 (LRRK2)-mediated neuronal cell death and wherein the Parkinson's disease is associated with a genetic mutation in the LRRK2 gene. 
     
     
         10 . (canceled) 
     
     
         11 . 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. 
     
     
         12 . The method of  claim 4 , 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. 
     
     
         13 . (canceled) 
     
     
         14 . A method of treating Parkinson's Disease (PD) in a 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 p53-inducible gene 3 (PIG3) (PIG3 inhibitor) in combination with an inhibitor of glucosylceramide synthase (GCS inhibitor), wherein the PIG3 inhibitor inhibits PIG3 by associating or binding to PIG3 protein, wherein the inhibitor comprises a peptide or a polypeptide, and wherein the subject has an increased expression level of PIG3, thereby treating the Parkinson's disease in the subject. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 14 , wherein the GCS inhibitor is selected from the group consisting of GZ/SAR402671 and GZ667161. 
     
     
         17 . The method of  claim 1 , wherein at least one symptom of PD is alleviated in the subject. 
     
     
         18 . The method of  claim 17 , wherein the at least one symptom of PD is selected from the group consisting of tremor, bradykinesia, muscle rigidity, reduction in speech and swallowing problems. 
     
     
         19 . 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. 
     
     
         20 .- 24 . (canceled) 
     
     
         25 . The method of  claim 1 , wherein the PIG3 modulator is an antibody or antigen-binding fragment thereof. 
     
     
         26 . The method of  claim 8 , wherein the PIG3 modulator is an antibody or antigen-binding fragment thereof. 
     
     
         27 . The method of  claim 9 , wherein the genetic mutation in the GBA gene is selected from the group consisting of N370S mutation and L444P mutation. 
     
     
         28 . The method of  claim 9 , 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. 
     
     
         29 . The method of  claim 14 , wherein the PIG3 modulator is an antibody or antigen-binding fragment thereof. 
     
     
         30 . The method of  claim 14 , 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.