Preventing Myocardial Loss and Sudden Death in Patients with Arrhythmogenic Cardiomyopathy via Rescuing of AIF/thioredoxin-2 Signaling

Case ID:
C15089

Unmet Need

About 400,000 to 460,000 people die each year from sudden cardiac death (SCD). Patients with Arrhythmogenic Cardiomyopathy (ACM) are at increased risk for heart failure and SCD triggered by exercise. Common ACM driver mutations occur in about 1 out of every 10,000 people. However, the physiological mechanisms that drive myocardial loss and lead to heart failure in ACM patients are not well known. Current standard of care for ACM patients seeks to manage the symptoms and to prevent SCD such as through activity restriction or implantable cardiac devices, rather than address the underlying pathological drivers of ACM progression. Thus, there is an imperative need for therapeutic targets that could treat ACM and improve patient outcome.

 

Technology Overview

The Johns Hopkins inventors have identified the AIF/thioredoxin-2 signaling pathway as a potential therapeutic target for ACM patients. The novel mechanism reveals that enhanced levels of apoptosis-inducing factor (AIF) translocating into the nucleus is associated with increased myocyte death. This translocation is prompted by altered redox balance in ACM hearts that is exacerbated by exercise. Inhibition of binding of AIF to nuclear chaperones that mediate translocation by AIF peptide mimetics prevents myocyte cell death. Discovery of this pathway, and its implications in ACM pathophysiology, expands the space of druggable targets to slow myocardial loss and progression of ACM.

 

Stage of Development

The inventors have studied this mechanism in a mouse model of ACM. They have identified and tested a set of peptides that have pharmacologic activity to disrupt the AIF/thioredoxin-2 signaling pathway.

  

Publication

Chelko SP, Keceli G, etal. Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy. Sci Transl Med. 2021 Feb 17;13(581):eabf0891. doi: 10.1126/scitranslmed.abf0891. PMID: 33597260.

Patent Information:
Title App Type Country Serial No. Patent No. File Date Issued Date Expire Date Patent Status
BINDING PEPTIDES AND USES THEREOF PCT: Patent Cooperation Treaty United States 18/275,586   8/2/2023     Pending
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For Information, Contact:
Vera Sampels
vsampel2@jhu.edu
410-614-0300
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