Precision medicine for Long QT Syndrome

Long QT Syndrome (LQTS) is a risk factor for dangerous cardiac arrhythmia and sudden cardiac death, with mutations in IKs channels being the leading cause.

Each year sudden cardiac death caused by congenital LQTS occurs in 130 cases per 100,000 people, most of which occur in children and young adults.

There is a clinical need for a safe drug that reduces the QT interval and, thereby, prevents cardiac arrhythmia and sudden cardiac deaths.Simulations have suggested that activators of IKs channels are the most effective and safest way to treat LQTS. At present, there are no approved IKs channel activators to treat LQTS.

We propose to develop small-molecule IKs activators to treat patients with mutations that cause cardiac arrhythmia.We have previously developed a group of compounds that activate IKs channels and act anti-arrhythmically. We hypothesize that further development of these compounds will lead to novel activators of IKs channels.

This “personalized-medicine” approach to treating cardiac arrhythmia is expected to drastically improve the clinical outcome of these patients and prevent sudden cardiac deaths caused by a variety of ion channel mutations.Aims:To develop novel potent and specific activators of IKsTo determine whether our novel IKs activators restore the action potential duration in human cardiomyocytes with LQTS mutations.Determine the anti-arrhythmic potential of our novel IKs activators in LQTS zebrafish ex vivo on isolated whole hearts and in vivo.