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.