Treatment and prevention of capillary malformation-arteriovenous malformation

Patent metadata

Field	Value
Publication number	US-12472189-B2
Application number	US-202117798502-A
Country	US
Kind code	B2
Filing date	Feb 12, 2021
Priority date	Feb 12, 2020
Publication date	Nov 18, 2025
Grant date	Nov 18, 2025

Abstract

Provided herein are methods for the treatment and prevention of vascular lesions arising from RASA1 and/or EPHB4 mutations and associated with capillary malformation-arteriovenous malformation (CM-AVM).

First claim

The invention claimed is:

1 . A method of treating or preventing capillary malformation-arteriovenous malformation (CM-AVM) comprising administering to a subject a pharmaceutical composition that promotes proper folding, and therefore export of, collagen IV from endothelial cells.

2 . The method of claim 1 , wherein the pharmaceutical composition comprises a chaperone molecule the facilitates proper folding of collagen IV, thereby allowing export of collagen from the endoplasmic reticulum and from the endothelial cells.

3 . The method of claim 2 , wherein the chaperone molecule is selected from 4-phenylbutyric acid (PBA), tauroursodeoxycholic acid (TUDCA), and ursodeoxycholic acid (UDCA).

4 . The method of claim 1 , wherein the pharmaceutical composition comprises an inhibitor of a collagen IV modifying enzyme that prevents over modification of collagen IV that leads to collagen IV accumulation in the ER and/or retaining of collagen IV within endothelial cells.

5 . The method of claim 4 , wherein the collagen IV modifying enzyme comprises a 2-oxoglutarate dependent collagen IV modifying enzymes.

6 . The method of claim 5 , wherein the inhibitor is selected from:

7 . The method of claim 1 , wherein the pharmaceutical composition comprises an inhibitor of an enzyme of a signaling pathway that is downstream from RASA1 and/or EPHB4.

8 . The method of claim 7 , wherein the pharmaceutical composition comprises an inhibitor of a mitogen-activated protein kinase (MAPK).

9 . The method of claim 8 , wherein the inhibitor is selected from:

10 . The method of claim 1 , wherein the pharmaceutical composition is administered to a subject that carries a germline mutation of RASA1 (RAS p21 protein activator 1).

11 . The method of claim 1 , wherein the pharmaceutical composition is administered to a subject that carries a germline mutation of EPHB4 (Ephrin type-B receptor 4).

12 . The method of claim 1 , wherein the subject suffers from CM-AVM and the pharmaceutical composition is administered to treat CM-AVM or symptoms thereof.

13 . The method of claim 1 , wherein the subject is at risk of developing CM-AVM and the pharmaceutical composition is administered to prevent CM-AVM or symptoms thereof.

14 . The method of claim 1 , wherein the subject is an adult female that carries a germline mutation that places offspring of the subject at risk for CM-AVM.

15 . The method of claim 14 , wherein the subject is pregnant, and the pharmaceutical composition is administered to prevent the offspring from developing CM-AVM.

16 . The method of claim 1 , further comprising a step of testing a subject for a germline mutation that renders susceptibility to CM-AVM.

17 . The method of claim 16 , wherein the subject is an infant or neonate.

18 . The method of claim 16 , wherein the subject is a female and is pregnant or pursuing pregnancy.

19 . The method of claim 1 , further comprising co-administering to the subject one or more agents that promote prenatal health and/or prevent development of birth defects in offspring of the subject.

Assignees

• The Regents Of Univ Of Michigan
• Univ Michigan Regents

Inventors

• King Philip
• Chen Di

Classifications

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• A61K31/4045

  Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin · CPC title

• A61K31/365

  Lactones · CPC title