Treating cardiovascular disease by selectively eliminating senescent cells

Patent metadata

Field	Value
Publication number	US-2021169875-A1
Application number	US-202017114376-A
Country	US
Kind code	A1
Filing date	Dec 7, 2020
Priority date	Jan 28, 2014
Publication date	Jun 10, 2021
Grant date	—

Abstract

Methods are provided herein for selectively killing senescent cells and for treating senescence-associated diseases and disorders by administering a senolytic agent. Senescence-associated diseases and disorders treatable by the methods using the senolytic agents described herein include cardiovascular diseases and disorders associated with or caused by arteriosclerosis, such as atherosclerosis; idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease; osteoarthritis; senescence-associated ophthalmic diseases and disorders; and senescence-associated dermatological diseases and disorders.

First claim

1 . A method of selectively eliminating senescent cells in an atherosclerotic plaque with a senolytic agent that is a Bcl inhibitor, wherein the Bcl senolytic agent is administered to the senescent cells in the atherosclerotic plaque intermittently, wherein the intermittent administration is a treatment cycle followed by a non-treatment interval.

2 . The method of claim 1 , wherein the Bcl senolytic agent is a Bcl-2 and Bcl-xL inhibitor or a Bcl-xL selective inhibitor.

3 . The method of claim 1 , wherein the Bcl senolytic agent is a small molecule inhibitor.

4 . The method of claim 1 , wherein the Bcl senolytic agent is a polynucleotide or oligonucleotide.

5 . The method of claim 4 , wherein the Bcl senolytic agent that is a polynucleotide or oligonucleotide is an antisense oligonucleotide, siRNA or shRNA.

6 . The method of claim 5 , wherein the non-treatment interval is between at least about 0.5 to 12 months.

7 . The method of claim 3 , wherein the small molecule inhibitor is administered to the senescent cells in the atherosclerotic plaque intermittently, wherein the intermittent administration is a treatment cycle followed by a non-treatment interval.

8 . The method of claim 7 , wherein the non-treatment interval is between at least about 0.5 to 12 months.

9 . The method of claim 5 , wherein the antisense oligonucleotide is administered to the senescent cells in the atherosclerotic plaque intermittently, wherein the intermittent administration is a treatment cycle followed by a non-treatment interval.

10 . The method of claim 9 , wherein the non-treatment interval is between at least about 0.5 to 12 months.

11 . The method of claim 8 , wherein the Bcl senolytic agent increases the fibrous cap thickness of the plaque.

12 . The method of claim 10 , wherein the Bcl senolytic agent increases the fibrous cap thickness of the plaque.

13 . A method of treating a cardiovascular disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising an effective amount of a senolytic agent that is a Bcl inhibitor, wherein the senolytic agent is administered intermittently, wherein the intermittent administration is a treatment cycle followed by a non-treatment interval.

14 . The method of claim 13 , wherein the Bcl inhibitor is a Bcl-2 and Bcl-xL inhibitor or a Bcl-xL selective inhibitor.

15 . The method of claim 13 , wherein the senolytic agent is a small molecule inhibitor.

16 . The method of claim 13 , wherein the senolytic agent is a polynucleotide or oligonucleotide.

17 . The method of claim 16 , wherein the polynucleotide or oligonucleotide is an antisense oligonucleotide, siRNA or shRNA.

18 . The method of claim 13 , wherein the non-treatment interval is between at least about 0.5 to 12 months.

19 . The method of claim 15 , wherein the non-treatment interval is between at least about 0.5 to 12 months.

20 . The method of claim 16 , wherein the non-treatment interval is between at least about 0.5 to 12 months.

21 . The method of claim 18 , wherein the cardiovascular disease is selected from atherosclerosis, congestive heart failure, peripheral vascular disease, hypertension, or coronary artery disease.

22 . The method of claim 19 , wherein the cardiovascular disease is selected from atherosclerosis, congestive heart failure, peripheral vascular disease, hypertension, or coronary artery disease.

23 . The method of claim 20 , wherein the cardiovascular disease is selected from atherosclerosis, congestive heart failure, peripheral vascular disease, hypertension, or coronary artery disease.

24 . The method of claim 18 , wherein the senolytic agent increases the fibrous cap thickness of the plaque.

25 . The method of claim 19 , wherein the senolytic agent increases the fibrous cap thickness of the plaque.

26 . The method of claim 20 , wherein the senolytic agent increases the fibrous cap thickness of the plaque.

Assignees

• Buck Inst Res Aging
• Unity Biotechnology Inc
• Mayo Found Medical Education & Res

Inventors

• Laberge Remi-Martin
• Campisi Judith
• Davalos Albert
• Demaria Marco
• David Nathaniel
• Van Deursen Jan M A
• Baker Darren J
• Childs Bennett G

Classifications

• C12Q1/485

  involving kinase · CPC title

• C12N2503/02

  Drug screening · CPC title

• C12N2501/999

  Small molecules not provided for elsewhere · CPC title

• C12N2320/30

  Special therapeutic applications · CPC title

• C12N15/113

  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