Peptibodies as novel therapies in atrial fibrillation

Active Project Grant Awarded Last action

Award ID
R01HL163943
Recipient
Awarding agency
Obligated
$6,590,384

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 96% complete
Place of performance
Tampa, FL 33612, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Atrial fibrillation (AF) is the most common arrhythmia and its prevalence is rising alarmingly. IT is particularly challenging to treat persistent AF and to restore normal sinus rhythm with currently available antiarrhythmics. Therefore, novel ION channel blocking modalities are needed for the development of the next generation of antiarrhythmic pharmacotherapies in persistent AF. A hallmark of remodeling in the chronically fibrillating atria is the presence of a constitutively active, parasympathetic stimulation independent acetylcholine sensitive inward rectifier potassium current (IKACH). Constitutively active IKACH acts as a background inward rectifier conductance and can contribute to the shortening of the atrial effective refractory period, and consequently to the perpetuation of AF. We demonstrated earlier that IKACH blockade with the peptidotoxin tertiapinq, a 21-amino acid synthetic peptide blocker of IKACH originally isolated from the european honeybee venom, terminates persistent AF. We thus bioengineered, produced and characterized a novel, and potent IKACH blocking peptibody. Peptibodies are chimeras generated as fusion proteins of the fragment crystallizable (FC) domain of the human immunoglobulin G (IGG1) with a bioactive "warhead" peptide. Peptibodies combine the biologic/therapeutic activity of a given peptide, with the stability of monoclonal antibodies and are stable and safe molecules that are emerging as viable clinical therapies. Our IKACH blocking peptibody was constructed as a fusion protein between the FC fragment of human IGG1 and tertiapinq linked together by an octaglycine spacer. In this application, we propose to test the hypothesis that bioengineered peptibodies designed as potent and bioactive blockers of IKACH are antiarrhythmic in persistent AF. Our goals are: 1- to delineate the structural determinants for the peptibody's block of IKACH; 2- to determine the atrial specificity, electrophysiological safety and therapeutic potential of anti-IKACH peptibodies in a PIG model of persistent AF; and 3- to bioengineer next generation peptibodies that have increased IKACH potency and specificity. Successful accomplishment of our proposal should be a major step forward in the deliberate, innovative, and rational development of much needed and effective antifibrillatory agents based on bioengineering approaches that target ION channels important in the mechanism of a major cardiac disease.

Transactions

Action Obligated Date
Amendment $596,155
Amendment $60,926
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Amendment $548,335
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Amendment $48,811
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Amendment $620,596
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Original award $620,596
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Subawards

Subrecipient Amount Awarded
Centro Nacional De Investigaciones Cardiovasculares Carlos III (F.s.p.) Peptibodies as Novel Therapies in Atrial Fibrillation $131,220
Centro Nacional De Investigaciones Cardiovasculares Carlos III (F.s.p.) Peptibodies as novel therapies in atrial fibrillation. $131,220
Centro Nacional De Investigaciones Cardiovasculares Carlos III (F.s.p.) $145,800

Quick answers

Who received award R01HL163943?

R01HL163943 was awarded to University Of South Florida by National Heart Lung and Blood Institute (National Institutes of Health) on January 1, 2023.

How much is award R01HL163943 worth?

$6,590,384 has been obligated on R01HL163943.

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