Lysosomal protein targeting sequence and therapeutic applications of same

Patent metadata

Field	Value
Publication number	US-9738880-B2
Application number	US-201715399165-A
Country	US
Kind code	B2
Filing date	Jan 5, 2017
Priority date	Sep 25, 2013
Publication date	Aug 22, 2017
Grant date	Aug 22, 2017

Abstract

The present disclosure relates to methods of treating diseases states such as lysosomal storage diseases and/or neurodegenerative diseases. Also disclosed are one or more compositions that may be useful for one or more of the disclosed methods, including compositions that may comprise acid β-glucosidase (GCase) protein comprising one or more mutations, peptides of acid β-glucosidase, and DNA vectors and cell lines related to acid β-glucosidase peptides or proteins.

First claim

What is claimed is:

1. A composition comprising a peptide, wherein said peptide comprises an amino acid sequence comprising at least 90% sequence identity to residues 347 through 422 of a human glucocerebrosidase (GCase) as set forth in SEQ ID NO 2, wherein said peptide comprises one or more mutations of D399E, D405E, D409E or combinations thereof, and wherein said peptide binds to a Lysosomal Integral Membrane Protein 2 (LIMP-2) receptor.

2. The composition of claim 1 , wherein said peptide inhibits localization of GCase to a lysosome of a cell in which GCase is being synthesized.

3. The composition of claim 1 , wherein said isolated peptide increases secretion of endogenous GCase.

4. The composition of claim 1 , wherein said peptide comprises from about 76 to about 400 amino acid residues in length.

5. The composition of claim 1 , wherein said peptide comprises the mutation D399E.

6. The composition of claim 1 comprising a pharmaceutically acceptable excipient.

7. A method of treating a disorder related to a dysfunction in the GCase pathway comprising the step of administering the composition of claim 1 to a patient in need thereof.

8. The method of claim 7 , wherein said disorder comprises defective GCase activity.

9. The method of claim 8 , wherein said defective activity comprises decreased enzymatic activity.

10. The method of claim 7 , wherein said disorder comprises alpha-synuclein dysregulation.

11. The method of claim 7 , wherein said disorder is a lysosomal storage disease.

12. The method of claim 11 , wherein said lysosomal storage disease is selected from Gaucher disease, Fabry disease, Pompe disease, mucopolysaccharidoses, and multiple system atrophy.

13. The method of claim 7 , wherein said disorder is a neurodegenerative disorder.

14. The method of claim 13 , wherein said neurodegenerative disorder is selected from Parkinson disease, Alzheimer disease, and Lewy body dementia.

15. The method of claim 7 , wherein said method comprises the step of administering said therapeutic agent via intraventricular and/or stereotactic intracerebral injection.

16. The method of claim 7 , wherein said dysfunction in the GCase pathway results in a central nervous system disease wherein the pathogenesis of said disease results in plaques and/or disease states associated with plaques.

Assignees

• Children'S Hospital Medical Center

Inventors

• Grabowski Gregory A
• Liou Benjamin

Classifications

• C12N9/2402 Primary

  hydrolysing O- and S- glycosyl compounds (3.2.1) · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C12Y302/01045

  Glucosylceramidase (3.2.1.45), i.e. beta-glucocerebrosidase · CPC title