# Towards a targeted therapy for Hailey Hailey Disease

> **NIH NIH R03** · JOHNS HOPKINS UNIVERSITY · 2024 · $163,750

## Abstract

SUMMARY
Hailey Hailey Disease (HHD), also known as benign chronic pemphigus, is a rare, autosomal dominant skin
disorder that affects the adhesion of epidermal keratinocytes. HHD is characterized by painful, recurrent blistering
of the skin that occurs predominantly in skin folds such as armpits, groin and neck, accompanied by weeping,
crusting and frequent secondary fungal or bacterial infection. There is no specific therapy and symptoms are
generally treated topically with limited efficacy. As a result, HHD is frequently disabling and significantly
impacts the quality of life. HHD is caused by mutations in one allele of ATP2C1, the gene encoding the Secretory
Pathway Ca2+-ATPase SPCA1. However, the underlying disease driving mechanism is controversial and has been
variously attributed to haploinsufficiency, dominant negative functions or even localized loss of heterozygosity.
SPCA1 localizes uniquely to the Golgi apparatus where it is required to transport Ca2+ and Mn2+ ions into the
lumen for the proper sorting, processing and modification of cargo proteins. In keratinocytes, Ca2+ homeostasis
is central to differentiation, cell adhesion and barrier repair. Although not clearly understood, it is thought that
HHD is caused by disruption of desmosomal and adherens junctions (acantholysis) resulting from Ca2+ and/or
Mn2+ homeostasis defects. Despite the identification of this molecular genetic defect over two decades ago,
SPCA1 remains understudied and there has been no significant effort towards effective therapy for HHD. In
contrast, the structurally related Ca2+-ATPase SERCA has been successfully drugged with small molecule
activators, peptides and gene therapy vectors which are currently in clinical trials for the treatment of heart
disease, muscular dystrophy and other disorders. Encouraged by these recent developments, and in response to
FOA RFA-TR-22-030 for “Pilot Projects Investigating Understudied Proteins Associated with Rare Diseases” we
propose to develop a human keratinocyte model of mono-allelic mutation or deletion of ATP2C1 and clarify
disease mechanism (Aim 1) and test the efficacy of phenotype rescue with lentiviral mediated SPCA1 delivery
(Aim 2). If successful, these studies will pave the way for future therapeutic efforts to cure this rare and
debilitating disease.

## Key facts

- **NIH application ID:** 10885628
- **Project number:** 1R03TR005427-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** RAJINI RAO
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $163,750
- **Award type:** 1
- **Project period:** 2024-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885628

## Citation

> US National Institutes of Health, RePORTER application 10885628, Towards a targeted therapy for Hailey Hailey Disease (1R03TR005427-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10885628. Licensed CC0.

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