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Novel anti-arrhythmic and heart failure drugs that target the leak in the ryanodine receptor (RYR2) and uses thereof

A technology for arrhythmia and heart failure, which can be used in drug combinations, medical preparations containing active ingredients, and pharmaceutical formulations, and can solve problems such as limited treatment options.

Inactive Publication Date: 2007-06-13
THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, despite its clinical importance, therapeutic options for AF remain limited, in part due to the fact that its underlying molecular mechanisms are poorly understood

Method used

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  • Novel anti-arrhythmic and heart failure drugs that target the leak in the ryanodine receptor (RYR2) and uses thereof
  • Novel anti-arrhythmic and heart failure drugs that target the leak in the ryanodine receptor (RYR2) and uses thereof
  • Novel anti-arrhythmic and heart failure drugs that target the leak in the ryanodine receptor (RYR2) and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-F

[0393] Example 1-FKBP12.6-deficient mice

[0394] FKBP12.6-deficient mice were generated as described above (Wehrens et al., "FKBP12.6 deficiency and defective calcium release channel (lyanodine receptor) function associated with exercise-induced sudden cardiac death", Cell, 113 : 829-40, 2003). Briefly, a mouse genomic lambda-phage clone for the murine orthologue of human FK506-binding protein 12.6 (FKBP12.6) was isolated from the DBA / 11acJ library using a full-length murine cDNA probe . A targeting vector was designed to delete exons 3 and 4 containing the full coding sequence of murine FKBP12.6 by replacing the 3.5 kb murine genomic DNA with the PGK-neo selectable marker (Bennett et al., "Mouse FK506-binding protein (FKBP) 12.6 gene Identification and characterization", Mamm. Genome, 9: 1069-71, 1998). The 5.0-kb 5' fragment and the 1.9-kb 3' fragment were cloned into pJNS2, the backbone vector containing the PGK-neo and PGK-TK cassettes. DBA / lacJ embryonic stem (ES) ...

Embodiment 2

[0396] Example 2 - Telemetry recording and locomotor testing in mice

[0397] Maintain and study FKBP12.6 in accordance with protocols approved by the Institutional Animal Care and Use Committee of Columbia University + / + and FKBP12.6 - / - mice. Mice were anesthetized using 2.5% isoflurane inhalation anesthesia. Ambulatory animal ECG radiotelemetry recordings obtained >7 days after intraperitoneal implantation (Data Sciences International, St. Paul, MN) (Wehrens et al., "FKBP12.6 Deficiency and Defect Sexual calcium release channel (lanodine receptor) function", Cell, 113:829-40, 2003). For stress testing, mice were exercised to failure on an inclined treadmill and then injected with epinephrine (0.5-2.0 mg / kg) intraperitoneally (Wehrens et al., "FKBP12. 6 Defective and defective calcium release channel (lanodine receptor) function", Cell, 113:829-40, 2003). The resting heart rate of the ambulatory animals was averaged over 4 hours.

Embodiment 3

[0398] Example 3 - Expression of wild type and RyR2-S2809D mutant

[0399] Mutagenesis of the PKA target site was performed on RyR2 (RyR2-S2809D) as described above (Wehrens et al., "FKBP12.6-deficient and defective calcium release channel (lyanodine receptor) associated with exercise-induced sudden cardiac death Function", Cell, 113:829-40, 2003). Use Ca 2+ Phosphate precipitation HEK293 cells were co-transfected with 20 μg RyR2 wild-type (WT) or mutant cDNA and 5 μg FKBP12.6 cDNA. Vesicles containing RyR2 channels were prepared as described above (Wehrens et al., "FKBP12.6 deficiency and defective calcium release channel (lyanodine receptor) function associated with exercise-induced sudden cardiac death", Cell, 113:829 -40, 2003).

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Abstract

The present invention provides methods for limiting or preventing a decrease in the level of RyR2-bound FKBP12.6 in a subject. The present invention further provides methods for treating and preventing atrial and ventricular cardiac arrhythmias, heart failure, and exercise-induced sudden cardiac death in a subject. Additionally, the present invention provides use of JTV-519 in a method for limiting or preventing a decrease in the level of RyR2-bound FKBP12.6 in a subject who has, or is a candidate for, atrial fibrillation. Also provided are uses of 1,4-benzothiazepine derivatives in methods for treating and preventing atrial and ventricular cardiac arrhythmias and heart failure in a subject, and for preventing exercise-induced sudden cardiac death. The present invention also provides methods for identifying agents for use in treating and preventing atrial fibrillation and heart failure, and agents identified by these methods.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Continuing-in-Part Application Serial No. US 10 / 809,089 filed March 25, 2004; claims the benefit of US Continuing-in-Part Application Serial No. US 10 / 763,498 filed January 22, 2004; claims October 2003 The U.S. portion filed on the 7th continues to apply for the benefit of serial number US 10 / 680,988; the U.S. portion filed on June 26, 2003 is requested to continue the benefit of serial number US 10 / 608,723; the U.S. portion filed on November 5, 2002 is requested Continuing the benefit of serial number US 10 / 288,606; claiming the benefits of the US part continuation application serial number US 09 / 568,474 filed on May 10, 2000, which is the current US patent US 6,489,125 B1 issued December 3, 2002; The contents of these documents are incorporated herein by reference. [0003] Statement of Government Interest [0004] This invention was made with Government support under NIH Gran...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/553A61K31/554
CPCA61K31/554A61P43/00A61P9/00A61P9/04A61P9/06A61K31/553
Inventor A·R·马克司D·W·兰德瑞S·邓Z·Z·程
Owner THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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