# Treating Hyperkalemic Periodic Paralysis

> **NIH NIH F30** · WRIGHT STATE UNIVERSITY · 2024 · $53,974

## Abstract

Project Summary/Abstract
Hyperkalemic Periodic Paralysis (HyperKPP) is one of a family of inherited skeletal muscle diseases known as
the ion channelopathies. HyperKPP patients have mutations in the skeletal muscle Nav1.4 sodium channel.
Importantly, patients suffer intermittent attacks of muscle paralysis and weakness lasting from minutes to days.
Despite identification of the gene responsible, mechanisms underlying the attacks of weakness remain poorly
understood, and current therapies are only modestly effective and have side effects. A mouse model of
HyperKPP has been generated, which recapitulates the key aspects of the disorder in patients. The mouse
model will be used to identify mechanisms contributing to failure of excitation contraction coupling caused by
pathologic depolarization of the membrane potential. These correlated studies will range from ex vivo whole-
muscle force recordings down to measurement of Ca transients in single fibers. A new technique allows for
simultaneous, intracellular recordings of action potentials and Ca transients of single muscle fibers in an intact
muscle. The overall goal is to address currently poorly understood aspects of HyperKPP and to develop novel
strategies for better therapies. This will be done in three Specific Aims:
1) Determine the mechanisms underlying depolarization-induced failure of excitation contraction
coupling (ECC) in normal muscle: Pilot data suggests failure of ECC is more complex than previously
suspected. The proposed correlated studies will elucidate the events preceding failure of ECC.
2) Determine the extent to which depolarization of the membrane potential contributes to failure of ECC
in HyperPP. The proposed studies will determine whether excessive depolarization of mutant muscle can fully
account for weakness. A series of electrophysiology experiments in HyperKPP vs. wild-type mice will address
this fundamental question.
3) Examine block of depolarizing current with a more selective blocker as an effective therapy for
HyperKPP. If the primary cause of HyperKPP is muscle depolarization, blocking the depolarizing current
should provide effective therapy. However, clinical studies suggest that the current Na channel blockers are
not effective in patients.
Identification of mechanisms contributing to depolarization-induced weakness in HyperKPP has implications for
all diseases in which depolarization of muscle contributes to weakness. If effective therapies are found to treat
weakness in the mouse model of HyperkPP, future work will be directed at translating findings to clinical trials
in patients.

## Key facts

- **NIH application ID:** 10906368
- **Project number:** 5F30AR081675-03
- **Recipient organization:** WRIGHT STATE UNIVERSITY
- **Principal Investigator:** Christopher Dupont
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 5
- **Project period:** 2022-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906368

## Citation

> US National Institutes of Health, RePORTER application 10906368, Treating Hyperkalemic Periodic Paralysis (5F30AR081675-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10906368. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*