Protease-activated receptor-2 inhibitors for the treatment of sensory neuropathy induced by a marine neurotoxic poisoning

Patent metadata

Field	Value
Publication number	US-12350260-B2
Application number	US-202017600977-A
Country	US
Kind code	B2
Filing date	Apr 5, 2020
Priority date	Apr 5, 2019
Publication date	Jul 8, 2025
Grant date	Jul 8, 2025

Abstract

The present invention relates to the treatment of sensory neuropathy induced by a marine neurotoxic poisoning. The invention further encompasses an in vitro method for producing a neuro-cutaneous model allowing to study the cellular and/or molecular mechanisms involved in said neuropathy, a neuro-cutaneous model obtainable according to said method, and applications thereof.

First claim

The invention claimed is:

1. A method for treating a sensory neuropathy induced by poisoning with a marine sodium-activating neurotoxin in a subject in need thereof, said method comprising administering a therapeutically effective amount of a protease-activated receptor-2 (PAR-2) inhibitor to the subject.

2. The method according to claim 1 , wherein said sensory neuropathy is pruritus, paresthesia, dysesthesia, allodynia, myalgia, arthralgia, dysuria, dental pain, or a combination thereof.

3. The method according to claim 1 , wherein said sensory neuropathy is mediated via activation of a voltage-gated sodium channel (VGSC) by the marine sodium-activating neurotoxin.

4. The method according to claim 1 , wherein said marine sodium-activating neurotoxin binds to an alpha subunit of a voltage-dependent sodium channels.

5. The method according to claim 1 , wherein said marine sodium-activating neurotoxin comprises a ciguatoxin (CTX), a brevetoxin (PbTx), an active metabolite thereof, or a combination thereof.

6. The method according to claim 1 , wherein said PAR-2 inhibitor is a PAR-2 full antagonist or a PAR-2 biased antagonist.

7. The method according to claim 1 , wherein said PAR-2 inhibitor is selected from the group consisting of a small molecule, a peptide, a polypeptide, a polynucleotide, and a combination thereof.

8. The method according to claim 1 , wherein said PAR-2 inhibitor is selected from the group consisting of GB83, GB88, and a derivative thereof.

9. The method according to claim 1 , wherein said PAR-2 inhibitor inhibits Cathepsin-S-mediated PAR-2 signaling.

10. The method according to claim 1 , wherein said PAR-2 inhibitor is selected from the group consisting of the Cathepsin S inhibitor Cbz-Phe-Leu-COCHO, and a derivative thereof.

11. The method according to claim 1 , wherein said PAR-2 inhibitor is in a pharmaceutical composition.

12. The method according to claim 2 , wherein said sensory neuropathy is mediated via activation of a VGSC by the marine sodium-activating neurotoxin.

13. The method according to claim 2 , wherein said marine sodium-activating neurotoxin binds to an alpha subunit of a voltage-dependent sodium channel.

14. The method according to claim 3 , wherein said marine sodium-activating neurotoxin binds to an alpha subunit of a voltage-dependent sodium channel.

15. The method according to claim 2 , wherein said marine sodium-activating neurotoxin comprises a ciguatoxin (CTX), a brevetoxin (PbTx), an active metabolite thereof, or a combination thereof.

16. The method according to claim 1 , wherein said PAR-2 inhibitor is a PAR-2 full antagonist.

17. The method according to claim 7 , wherein said PAR-2 inhibitor is selected from the group consisting of a pepducin, an antibody, a RNAi, an aptamer, and a combination thereof.

Assignees

• Univ Bretagne Occidentale
• Centre Hospitalier Regional Et Univ De Brest
• Inst Nat Sante Rech Med

Inventors

• Le Garrec Raphaele
• L'Herondelle Killian
• Misery Laurent
• Pierre Ophelie
• Mignen Olivier

Classifications

• G01N33/5023

  on expression patterns · CPC title

• C12N2502/094

  keratinocytes · CPC title

• C12N2502/083

  sensory transducers · CPC title

• C12N2501/999

  Small molecules not provided for elsewhere · CPC title

• C12N2501/33

  Insulin · CPC title