Autophagy as a therapeutic target for intracranial aneurysm

Patent metadata

Field	Value
Publication number	US-12116597-B2
Application number	US-202217824621-A
Country	US
Kind code	B2
Filing date	May 25, 2022
Priority date	Jan 5, 2022
Publication date	Oct 15, 2024
Grant date	Oct 15, 2024

Abstract

Disclosed here are uses of autophagy inhibitors for treating a subject at risk of suffering from an aneurysm. The present disclosure demonstrates that autophagy plays a role in THSD1-mediated focal adhesion stability and aneurysm formation and characterizes molecular targets for therapeutic intervention.

First claim

We claim:

1. A method for treating a human subject at risk of suffering from an intracranial aneurysm comprising administering to said human subject a therapeutically effective dose of an autophagy inhibitor, wherein the autophagy inhibitor is selected from the group consisting of wortmannin, chloroquine, clomipramine, 3-Methyladenine, Bafilomycin A1, Pepstatin A, and Pepstatin E-64-d, wherein the human subject carries a variant affecting the expression of a Thrombospondin Type 1 Domain Containing 1 (THSD1) gene.

2. The method of claim 1 , wherein the autophagy inhibitor is wortmannin.

3. The method of claim 1 , wherein the autophagy inhibitor is chloroquine.

4. The method of claim 1 , wherein the autophagy inhibitor is clomipramine.

5. The method of claim 1 , wherein the autophagy inhibitor is 3-Methyladenine.

6. The method of claim 1 , wherein the autophagy inhibitor is Bafilomycin A1.

7. The method of claim 1 , wherein the autophagy inhibitor is Pepstatin A.

8. The method of claim 1 , wherein the autophagy inhibitor is Pepstatin E-64-d.

9. The method of claim 1 , wherein the variant is in a coding region of the Thrombospondin Type 1 Domain Containing 1 (THSD1) gene.

10. The method of claim 1 , wherein the variant is in a control sequence of a non-coding region of the Thrombospondin Type 1 Domain Containing 1 (THSD1) gene.

11. The method of claim 1 , wherein the variant in the THSD1 gene is a single codon substitution in at least one THSD1 allele.

12. The method of claim 1 , wherein the single codon substitution is L5F, R460W, E466G, G600E, P639L, T653I, or S775P.

13. The method of claim 1 , wherein the therapeutically effective dose of the autophagy inhibitor is administered systemically.

14. The method of claim 13 , wherein systemic administration comprises: (i) intravenous, (ii) intra-arterial; (iii) subcutaneous; or (iv) intraperitoneal.

15. The method of claim 1 , wherein the therapeutically effective dose of the autophagy inhibitor is administered locally.

16. The method of claim 15 , wherein local administration includes, but is not limited to, (i) intracranial; (ii) intra-ocular; (iii) intra-nasal; (iv) intrathecal or (v) intra-vascular.

Assignees

• Univ Texas

Inventors

• Kim Dong H
• Rui Yanning
• Xu Zhen
• Hagan John

Classifications

• A61K38/10

  Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title

• A61K31/4706

  4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine · CPC title

• A61K31/37

  Coumarins, e.g. psoralen · CPC title