Modulating phosphatase activity in cardiac cells

Patent metadata

Field	Value
Publication number	US-2018296578-A1
Application number	US-201615065507-A
Country	US
Kind code	A1
Filing date	Mar 9, 2016
Priority date	Sep 9, 2004
Publication date	Oct 18, 2018
Grant date	—

Abstract

Expression of a phosphatase inhibitor in heart cells can be used to treat cardiac disorders, e.g., heart failure. Decreasing phosphatase activity can improve β-adrenergic responsiveness.

First claim

1 . A method of treating a subject having heart failure, comprising:
introducing, into heart cells of the subject, a nucleic acid that comprises a sequence encoding a phosphatase inhibitor protein that inhibits phosphatase activity, in an amount effective to decrease phosphatase activity and thereby increase β-adenergic responsiveness.

2 . The method of claim 1 wherein the phosphatase inhibitor protein inhibits type 1 phosphatases.

3 . The method of claim 1 wherein the phosphatase inhibitor protein is a full length protein.

4 . The method of claim 1 wherein the phosphatase inhibitor protein is a constitutively active fragment.

5 . The method of claim 1 wherein the phosphatase inhibitor protein is phosphatase inhibitor-1 or a fragment thereof.

6 . The method of claim 5 wherein the phosphatase inhibitor protein is a constitutively active fragment of phosphatase inhibitor-1.

7 . The method of claim 5 wherein the phosphatase inhibitor-1 protein has threonine at position 35.

8 . The method of claim 5 wherein the phosphatase inhibitor-1 protein has aspartic acid at position 35 (T35D).

9 . The method of claim 5 wherein the phosphatase inhibitor protein comprises amino acids 1-65 of phosphatase inhibitor-1, aspartic acid at position 35 (T35D), and is truncated at or before amino acid 171, 90, 70, 67, 66, 65, 61, or 54.

10 . The method of claim 5 wherein the nucleic acid further comprises a promoter operably linked to the coding sequence.

11 . The method of claim 10 wherein the promoter is a constitutive promoter.

12 . The method of claim 10 wherein the promoter is expressed in a subset of tissues, at least one of which is a cardiac muscle.

13 . The method of claim 10 wherein the promoter comprises regulatory sequences from the Cytomegalovirus (CMV) or the cardiac specific cardiac troponin T, myosin heavy chain or the myosin light chain.

14 . The method of claim 1 wherein the nucleic acid is introduced using a viral particle.

15 . The method of claim 14 wherein the nucleic acid is introduced using a lentiviral particle.

16 . The method of claim 14 wherein the nucleic acid is introduced using an adeno-associated viral particle.

17 . The method of claim 16 wherein the AAV particle is serotype AAV6.

18 . The method of claim 1 wherein the nucleic acid is introduced in an amount effective to result in myocyte shortening, to lower the time constant for relaxation, tau (T), to accelerate calcium signal decay.

19 . The method of claim 1 wherein the nucleic acid is introduced in an amount effective to increase in phosphorylation of serine 16 of phospholamban.

20 . The method of claim 1 wherein the nucleic acid is introduced in an amount effective to improve the end-systolic pressure dimension relationship.

21 - 38 . (canceled)

Assignees

• The Univ Of Cincinnati
• Massachusetts Gen Hospital
• The Us Secretary Department Of Health & Human Servic
• The Us Secretary Department Of Health & Human Services

Inventors

• Hajjar Roger J
• Del Monte Federica
• Kranias Evangelia

Classifications

• A61P3/14

  for calcium homeostasis (vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04) · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/06

  Antiarrhythmics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title