# Domain-specific gating modulation to restore action potential duration in long QT patient-derived cardiomyocytes

> **NIH NIH R00** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $241,284

## Abstract

PROJECT SUMMARY/ABSTRACT
The human ether-a-go-go gene (hERG) and KCNQ1 genes encode proteins that conduct the cardiac
repolarizing currents IKr and IKs, respectively. Impaired repolarization increases the risk of potentially lethal
ventricular arrhythmias and is a hallmark of long QT syndrome (LQTS) and heart failure. Treatments for
impaired repolarization are limited largely due to their high incidence of off-target effects. hERG cytoplasmic
domains interact to negatively modulate IKr, making them potential targets to treat diseases of repolarization.
The preliminary data for this grant demonstrate that small antibody peptide fragments targeting distinct regions
of the cytoplasmic hERG Per-Arnt-Sim (PAS) domain selectively increase IKr and shorten action potential
duration (APD). As a therapeutic, such fragments would potentially shorten APD and restore impaired
repolarization in LQTS and heart failure. Additionally, antibody fragments directed toward the PAS and other
domains would be useful tools to characterize how specific gating processes regulate cellular behavior and
overall cardiac physiology. In the mentored phase of this project, I will characterize the mechanisms by which
these antibody fragments modify hERG gating using electrophysiological and spectroscopy techniques. I will
also characterize antibody fragment hERG modulation in healthy human stem cell-derived cardiomyocytes
(iPSC-CMs) and iPSC-CMs obtained from LQTS patients using scFvs delivered intracellularly via the recording
pipette. In the independent phase of this project, I will combine the scFv antibodies with two intracellular
delivery techniques: (1) the cell-penetrating Cardiac Targeting Peptide, CTP, and (2) the adeno-associated
virus serotype 9 (AAV9). I will introduce antibody-CTP fusion proteins into iPSC-CMs and monitor the resulting
biophysical and physiological effects with patch clamp and micro-electrode techniques. To develop an
approach leading to a longer-term treatment, I will use the viral AAV9 to produce stable transfer of the
antibody-encoding sequence into mammalian cardiomyocytes. These experiments will generate novel tools to
probe the mechanistic role of distinct channel processes in native physiology. Additionally, these experiments
will act as a proof-of-concept for future experiments designed to develop anti-hERG antibody fragments into
treatments for impaired repolarization. This proposal is designed to fulfill my short-term goals of expanding my
skills in cardiac electrophysiology and transitioning into the independent phase of my career. This will
ultimately allow me to obtain my long-term goal of studying translational cardiac electrophysiology research by
using patient-derived iPSC-CMs to explore triggers and treatments for cardiac arrhythmia.

## Key facts

- **NIH application ID:** 9997991
- **Project number:** 5R00HL133482-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** David K. Jones
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $241,284
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997991

## Citation

> US National Institutes of Health, RePORTER application 9997991, Domain-specific gating modulation to restore action potential duration in long QT patient-derived cardiomyocytes (5R00HL133482-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9997991. Licensed CC0.

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