Treatment of Synucleinopathies

Patent metadata

Field	Value
Publication number	US-2016199461-A1
Application number	US-201615079709-A
Country	US
Kind code	A1
Filing date	Mar 24, 2016
Priority date	May 16, 2007
Publication date	Jul 14, 2016
Grant date	—

Abstract

This invention relates generally to treating synucleinopathies in subjects that are not clinically diagnosed with a lysosomal storage disease, as well as associated methods of making medicaments and screening methods.

First claim

What is claimed is:

1 . A method of treating a subject with a synucleinopathy, but not a clinically diagnosed lysosomal storage disease, the method comprising administering to a subject any one or more of:
an acid-beta-glucocerebrosidase (GBA) polypeptide, a polynucleotide encoding an acid-beta-glucocerebrosidase (GBA) polypeptide, a GBA polypeptide activating polypeptide, a polynucleotide encoding a GBA polypeptide activating agent, a cathepsin D polypeptide, a procathepsin D polypeptide, and a polynucleotide encoding a cathepsin D or procathepsin D polypeptide, in an amount effective to reduce a level of α-synuclein in the subject's central or peripheral nervous system, or both, or in the subject's lysosomal compartment.

2 . The method of claim 1 , wherein the synucleinopathy is a primary synucleinopathy.

3 . The method of claim 2 , wherein the synucleinopathy comprises any one or more of: Parkinson's disease (PD); sporadic or heritable dementia with Lewy bodies (DLB); pure autonomic failure (PAF) with α-synuclein deposition; multiple system atrophy (MSA); hereditary neurodegeneration with brain iron accumulation; and incidental Lewy body disease of advanced age.

4 . The method of claim 1 , wherein the synucleinopathy is a secondary synucleinopathy.

5 . The method of claim 4 , wherein the synucleinopathy comprises any one or more of: Alzheimer's disease of the Lewy body variant; Down's syndrome; progressive supranuclear palsy; essential tremor with Lewy bodies; familial parkinsonism with or without dementia; tau gene and progranulin gene-linked dementia with or without parkinsonism; Creutzfeldt Jakob disease; bovine spongiform encephalopathy; secondary Parkinson disease; parkinsonism resulting from neurotoxin exposure; drug-induced parkinsonism with α-synuclein deposition; sporadic or heritable spinocerebellar ataxia; amyotrophic lateral sclerosis (ALS); and idiopathic rapid eye movement sleep behavior disorder.

6 . The method of claim 1 , wherein the GBA activating polypeptide comprises any one or more of a prosaposin polypeptide, a saposin A polypeptide, a saposin B polypeptide, a saposin C polypeptide, and a saposin D polypeptide.

7 . The method of claim 6 , wherein the GBA activating polypeptide comprises a saposin C polypeptide.

8 . The method of claim 1 , wherein the polynucleotide encoding a GBA activating polypeptide comprises a polynucleotide encoding any one or more of a prosaposin polypeptide, a saposin A polypeptide, a saposin B polypeptide, a saposin C polypeptide, and a saposin D polypeptide.

9 . The method of claim 1 , further comprising administering one or more agents that enhance autophagy of α-synuclein complexes.

10 . The method of claim 9 , wherein the agent comprises an mTOR inhibitor.

11 . The method of claim 9 , wherein the agent comprises rapamycin or a rapamycin analog.

12 . The method of claim 9 , wherein the agent comprises one or more of everolimus, cyclosporine, FK506, hsc70, N-octyl-4-epi-β-valienamine, and glycerol.

13 . The method of claim 9 , wherein the agent comprises a small molecule, a large molecule, a peptide, an antibody, a nucleic acid, or a biologically active fragment thereof.

14 . Use of any one or more of
an acid-beta-glucocerebrosidase (GBA) polypeptide, a polynucleotide encoding an acid-beta-glucocerebrosidase (GBA) polypeptide, a GBA polypeptide activating polypeptide, a polynucleotide encoding a GBA polypeptide activating agent, a cathepsin D polypeptide, a procathepsin D polypeptide, and a polynucleotide encoding a cathepsin D or procathepsin D polypeptide, in a method of preparing a medicament for the treatment of a synucleinopathy.

Assignees

• Brigham & Womens Hospital

Inventors

• Schlossmacher Michael
• Shihabuddin Lamya
• Cheng Seng H
• Cullen Valerie

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P31/02

  Local antiseptics · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title