Granted Patent
B2
US 12,472,189 · App. 17/798,502 · Granted Nov 18, 2025
Treatment and prevention of capillary malformation-arteriovenous malformation
A61K31/575A61K31/167A61K31/192A61K31/194A61K31/198A61K31/275A61K31/277A61K31/352A61K31/365A61K31/4045A61K31/4184A61K31/44A61K31/5377A61P9/14
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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).
Claims (19)
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.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 30, 2022
From: KING, PHILIP; CHEN, DI
To: THE REGENTS OF THE UNIVERSITY OF MICHIGAN
Reel/Frame 060942/0582 →
Continuity (2)
Provisional Application
62975524
· Feb 12, 2020
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