ATP1A3-Related Disorders in Brazil: Natural History and Antisense Oligonucleotide Therapy Development

Project Summary ATP1A3-related disorders are a group of disorders caused by mutations in the ATP1A3 gene that encodes the α3 catalytic subunit of Na+/K+-ATPase transmembrane ion pump. Three classic phenotypes are known, which are alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism (RDP), and cerebellar

ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS). These conditions all carry significant neurological morbidity and there is no effective treatment. They are rare disorders but the prevalence of AHC may be as high as 1/100,000. Development of novel therapies is urgently needed.

In order to achieve disease-modifying treatment in this condition, we need to: 1) fully understand the genotype-phenotype correlation and natural history of the disease, 2) have a patient population that is ready for clinical trial, and 3) have a novel treatment modality. In this project, we will achieve these goals by studying

ATP1A3-related disorders in Brazil. Taking advantage of a large clinical whole-exome database in Brazil, we aim to build a first large cohort of patients with ATP1A3-related disorders in Latin America. We will analyze genotype- phenotype correlation and collect biospecimens from patients for induced pluripotent stem cell (iPSC) generation

and biomarker identification, and two-year natural history study will prepare the population for future clinical trials. At the same time, we will develop allele-specific oligonucleotides (ASOs) against pathogenic ATP1A3 mutations or benign single nucleotide polymorphisms that are linked to pathogenic ATP1A3 mutations to knockdown

mutant ATP1A3 mRNA. iPSCs from Brazilian patients will be used as a platform for ASO development. All aspects of this project will be done in close collaboration between the Brazilian and US researchers. This proposed project holds great significance because: 1) ATP1A3-related disorders are a condition with

significant morbidity and mortality without effective treatment, 2) this first systematic clinical study of the condition in Brazil will lead to new insights into natural history and genotype-phenotype correlation of the disease, 3) the study will prepare the Brazilian patients for future clinical trials, 4) novel ASO treatment will be applicable not

only to patients in Brazil but also worldwide, and 5) the study will help build research capacity for precision medicine in Brazil. Further, this proposed project is highly innovative because: 1) the unique, little studied patient population in Brazil fills the existing geographical gap in the study of this condition, 2) subject identification

through a clinical exome database will allow enrollment of individuals with atypical and novel phenotypes and informs the pathogenesis, 3) this study develops neurons differentiated from patient-derived iPSCs as an in vitro model and uses them as a platform for therapeutic development, which has not yet been commonly done in

ATP1A3-related disorders, 4) allele-specific ASOs represent a novel therapeutic approach for this condition, and 5) we will develop ASOs targeting pathogenic mutations as well as benign polymorphisms linked to pathogenic mutations, expanding the drug’s target population.