Therapeutic agent for glycogen storage disease type IA

Patent metadata

Field	Value
Publication number	US-11958878-B2
Application number	US-201916966132-A
Country	US
Kind code	B2
Filing date	Mar 5, 2019
Priority date	Mar 9, 2018
Publication date	Apr 16, 2024
Grant date	Apr 16, 2024

Abstract

The present invention establishes a molecular therapy for glycogen storage disease type Ia. The present invention provides an oligonucleotide of 15-30 bases comprising a nucleotide sequence complementary to die cDNA of G6PC gene with c.648G>T mutation, wherein the oligonucleotide comprises a sequence complementary to a region comprising any site between the 82 nd to the 92 nd nucleotide from the 5′ end of exon 5 of the G6PC gene with c.648C>T mutation, a pharmacologically acceptable salt or solvate thereof. Also provided is a pharmaceutical drug comprising the oligonucleotide, a pharmacologically acceptable salt or solvate thereof (e.g., therapeutic drug for glycogen storage disease type Ia).

First claim

The invention claimed is:

1. A conjugate of an oligonucleotide and a GalNAc unit or a pharmacologically acceptable salt or solvate thereof, wherein the conjugate is selected from:
5′-A m1s -A e2s -U m1s —C m1s -C e2s -G m1s -A m1s -T e2s -G m1s -G m1s -C e2s -G m1s -A m1s -A e2s -G m1t -H-3′ (SEQ ID NO: 40) and X 18 , wherein the X 18 is a GalNAc unit attached to the 5′ end of SEQ ID NO: 40,
5′-A e2s -U m1s —C m1s -C e2s -G m1s -A m1s -T e2s -G m1s -G m1s -C e2s -G m1s -A m1s -A e2s -G m1s -C e2t —H-3′ (SEQ ID NO: 171) and X 18 , wherein the X 18 is a GalNAc unit attached to the 5′ end of SEQ ID NO: 171,
5′-U m1s —C m1s -C e2s -G m1s -A m1s -T e2s -G m1s -G m1s -C e2s -G m1s -A m1s -A e2s -G m1s -C e2s —U m1t —H-3′ (SEQ ID NO: 172) and X 18 , wherein the X 18 is a GalNAc unit attached to the 5′ end of SEQ ID NO: 172,
5′-A m1s -A m1s -A e2s -U m1s —C m1s -C e2s -G m1s -A m1s -T e2s -G m1s -G m1s -C e2s -G m1s -A m1s -A e2s -G m1t -H-3′ (SEQ ID NO: 42) and X 18 , wherein the X 18 is a GalNAc unit attached to the 5′ end of SEQ ID NO: 42,
5′-A m1s -A e2s -U m1s —C m1s -C e2s -G m1s -A m1s -T e2s -G m1s -G m1s -C e2s -G m1s -A m1s -A e2s -G m1s -C e2t —H-3′ (SEQ ID NO: 47) and X 18 , wherein the X 18 is a GalNAc unit attached to the 5′ end of SEQ ID NO: 47,
5′-A e2s -U m1s —C m1s -C e2s -G m1s -A m1s -T e2s -G m1s -G m1s -C e2s -G m1s -A m1s -A e2s -G m1s -C e2s —U m1t —H-3′ (SEQ ID NO: 48) and X 18 , wherein the X 18 is a GalNAc unit attached to the 5′ end of SEQ ID NO: 48,
5′-A m1s -A e2s -U m1s —C m1s -C e2s -G m1s -A e2s -U m1s -G m1s -G m1s -C e2s -G m1s -A m1s -A e2s -G m1t -H-3′ (SEQ ID NO: 173) and X 18 , wherein the X 18 is a GalNAc unit attached to the 5′ end of SEQ ID NO: 173,
5′-A e2s -U m1s —C m1s -C e2s -G m1s -A e2s -U m1s -G m1s -G m1s -C e2s -G m1s -A m1s -A e2s -G m1s -C e2t —H-3′ (SEQ ID NO: 174) and X 18 , wherein the X 18 is a GalNAc unit attached to the 5′ end of SEQ ID NO: 174,
5′-U m1s —C m1s -C e2s -G m1s -A e2s -U m1s -G m1s -G m1s -C e2s -G m1s -A m1s -A e2s -G m1s -C e2s —U m1t —H-3′ (SEQ ID NO: 175) and X 18 , wherein the X 18 is a GalNAc unit attached to the 5′ end of SEQ ID NO: 175,
5′-A m1s -A m1s -A e2s -U m1s —C m1s -C e2s -G m1s -A e2s -U m1s -G m1s -G m1s -C e2s -G m1s -A m1s -A e2s -G m1t -H-3′ (SEQ ID NO: 176) and X 18 , wherein the X 18 is a GalNAc unit attached to the 5′ end of SEQ ID NO: 176,
5′-A m1s -A e2s -U m1s —C m1s -C e2s -G m1s -A e2s -U m1s -G m1s -G m1s -C e2s -G m1s -A m1s -A e2s -G m1s -C e2t —H-3′ (SEQ ID NO: 177) and X 18 , wherein the X 18 is a GalNAc unit attached to the 5′ end of SEQ ID NO: 177,
5′-A e2s -U m1s —C m1s -C e2s -G m1s -A e2s -U m1s -G m1s -G m1s -C e2s -G m1s -A m1s -A e2s -G m1s -C e2s —U m1t —H-3′ (SEQ ID NO: 178) and X 18 , wherein the X 18 is a GalNAc unit attached to the 5′ end of SEQ ID NO: 178,
5′-A m1s -A e2s -U m1s —C m1s —C e2s -G m1s -A e2s -U m1s -G m1s -G m1s -C e2s -G m1s -A m1s -A e2s -G m1t -H-3′ (SEQ ID NO: 173) and X 20 , wherein the X 20 is a GalNAc unit attached to the 5′ end of SEQ ID NO: 173,
5′-A e2s -U m1s —C m1s -C e2s -G m1s -A e2s -U m1s -G m1s -G m1s -C e2s -G m1s -A m1s -A e2s -G m1s -C e2t —H-3′ (SEQ ID NO: 174) and X 20 , wherein the X 20 is a GalNAc unit attached to the 5′ end of SEQ ID NO: 174,
5′-A m1s -A m1s -A e2s -U m1s —C m1s -C e2s -G m1s -A e2s -U m1s -G m1s -G m1s -C e2s -G m1s -A m1s -A e2s -G m1t -H-3′ (SEQ ID NO: 176) and X 20 , wherein the X 20 is a GalNAc unit attached to the 5′ end of SEQ ID NO: 176, and
5′-A m1s -A e2s -U m1s —C m1s -C e2s -G m1s -A e2s -U m1s -G m1s -G m1s -C e2s -G m1s -A m1s -A e2s -G m1s C e2t —H-3′ (SEQ ID NO: 177) and X 20 , wherein the X 20 is a GalNAc unit attached to the 5′ end of SEQ ID NO: 177,
wherein G m1t , U m1t , A m1s , G m1s , C m1s , U m1s , C e2t , A e2s , C e2s , T e2s , X 18 and X 20 are defined as follows:

wherein the atomic bonding to phosphate group in X 18 and X 20 comprises formation of a phosphodiester bond by binding to the carbon atom at the 5′ end of the oligonucleotide.

2. A pharmaceutical drug comprising the conjugate or a pharmaceutically acceptable salt or solvate thereof of claim 1 .

3. A therapeutic drug for glycogen storage disease type Ia, comprising the conjugate or a pharmaceutically acceptable salt or solvate thereof of claim 1 .

4. A formulation for oral or parenteral administration, comprising the conjugate or a pharmaceutically acceptable salt or solvate thereof of claim 3 .

5. A method of treating glycogen storage disease type Ia, comprising administering to a subject in need thereof a pharmaceutically effective amount of the conjugate or a pharmacologically acceptable salt or solvate thereof of claim 1 .

6. The method of claim 5 , wherein the subject has a G6PC c.648G>T mutation.

Assignees

• Daiichi Sankyo Co Ltd
• Kobe Gakuin Educational Found

Inventors

• Koizumi Makoto
• Onishi Yoshiyuki
• Masuda Takeshi
• Iwamoto Mitsuhiro
• Sekiguchi Yukiko
• Ito Kentaro
• TSUJI Shinnosuke
• Matsuo Masafumi

Classifications

• C07H21/02 Primary

  with ribosyl as saccharide radical · CPC title

• A61K31/711 Primary

  Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links · CPC title

• C12N15/113 Primary

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

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