Acid-alpha glucosidase variants and uses thereof

Patent metadata

Field	Value
Publication number	US-2019390184-A1
Application number	US-201716332373-A
Country	US
Kind code	A1
Filing date	Sep 12, 2017
Priority date	Sep 12, 2016
Publication date	Dec 26, 2019
Grant date	—

Abstract

The present invention relates to variants of acid-alpha glucosidase and uses thereof. Said variants are sequence-optimized and/or are linked to a heterogenous signal peptide.

First claim

1 - 13 . (canceled)

14 . A nucleic acid molecule encoding a functional chimeric GAA polypeptide, comprising the signal peptide of the human alpha-1-antitrypsin protein fused to a functional GAA polypeptide, wherein the functional GAA polypeptide is encoded by a nucleotide sequence having at least 85% identity to SEQ ID NO: 1 or SEQ ID NO: 2.

15 . The nucleic acid molecule according to claim 14 , wherein the nucleotide sequence encoding the functional GAA polypeptide comprises SEQ ID NO: 1 or SEQ ID NO: 2.

16 . A nucleic acid construct, comprising the nucleic acid molecule according to claim 14 , which is an expression cassette comprising said nucleic acid molecule operably linked to a promoter wherein said nucleic acid construct optionally further comprises an intron, wherein said intron is optionally a modified intron.

17 . The nucleic acid construct according to claim 16 , comprising: an enhancer; an intron; a promoter, the nucleic acid molecule encoding the chimeric GAA polypeptide; and a polyadenylation signal.

18 . The nucleic acid construct according to claim 17 , comprising: an ApoE control region; a HBB2 intron; the hAAT promoter; the nucleic acid molecule encoding the chimeric GAA polypeptide; and a bovine growth hormone polyadenylation signal.

19 . A vector comprising the nucleic acid molecule according to claim 14 .

20 . The vector according to claim 19 , which is a single-stranded or double-stranded self-complementary AAV vector.

21 . The vector according to claim 20 , wherein the AAV vector has an AAV8, AAV9, AAVrh74 or AAV2i8 capsid.

22 . A cell transformed with the nucleic acid molecule according to claim 14 .

23 . A chimeric GAA polypeptide encoded by the nucleic acid molecule according to claim 14 .

24 . A pharmaceutical composition, comprising, in a pharmaceutically acceptable carrier the chimeric GAA polypeptide according to claim 23 or a nucleic acid encoding said chimeric GAA polypeptide.

25 . A method of treating a glycogen storage disease comprising the administration of a nucleic acid molecule according to claim 14 , a nucleic acid construct comprising said nucleic acid molecule or a chimeric GAA polypeptide encoded by said nucleic acid molecule to a subject having a glycogen storage disease.

26 . The method according to claim 25 , wherein said glycogen storage disease is GSDI (von Gierke's disease), GSDII (Pompe disease), GSDIII (Cori disease), GSDIV, GSDV, GSDVI, GSDVII, or GSDVIII and lethal congenital glycogen storage disease of the heart.

Assignees

• Genethon
• Univ Sorbonne
• Univ Duke

Inventors

• Mingozzi Federico
• Ronzitti Giuseppe
• Koeberl Dwight D
• Han Sang-Oh

Classifications

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• C12N2750/14132

  Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent · CPC title

• C12N2750/14143

  viral genome or elements thereof as genetic vector · CPC title

• A61K38/47

  acting on glycosyl compounds (3.2), e.g. cellulases, lactases · CPC title