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

> **NIH NIH R21** · BOSTON CHILDREN'S HOSPITAL · 2024 · $372,970

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10987581
- **Project number:** 1R21NS139341-01
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** GANESHWARAN HITOSHI MOCHIDA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $372,970
- **Award type:** 1
- **Project period:** 2024-09-17 → 2026-09-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10987581

## Citation

> US National Institutes of Health, RePORTER application 10987581, ATP1A3-Related Disorders in Brazil: Natural History and Antisense Oligonucleotide Therapy Development (1R21NS139341-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10987581. Licensed CC0.

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