NIH grant: Novel Zebrafish Models and Molecular Insights into 4H Leukodystrophy, Linking POLR3 Dysfunction to Disease Progression and Therapeutic Compound Discovery (1RF1NS148634-01)

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NIH grant 1RF1NS148634-01: Novel Zebrafish Models and Molecular Insights into 4H Leukodystrophy, Linking POLR3 Dysfunction to Disease Progression and Therapeutic Compound Discovery
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Hung-Yu  Shih. Award: $1010605.
Start: 2026-09-25T00:00:00.
R01 ESI: Novel Zebrafish Models and Molecular Insights into 4H Leukodystrophy, Linking POLR3
 Dysfunction to Disease Progression and Therapeutic Compound Discovery
 Project Summary
4H leukodystrophy (4H) is a rare pediatric neurodegenerative disorder characterized by hypomyelination,
hypodontia, and hypogonadotropic hypogonadism. Although mutations in POLR3A, POLR3B, and POLR3K,
which encode subunits of the RNA polymerase III (POLR3) complex, are known to cause 4H, the mechanistic
link between POLR3 dysfunction and disease pathology remains poorly understood. This critical gap hampers
therapeutic development, and currently, no effective treatments are available. Current Polr3-deficient mouse
models are limited by a lack of neurological phenotypes, embryonic lethality, or reliance on tamoxifen-inducible
systems that ensure postnatal survival but delay the onset of phenotypic development. These constraints reduce
their practicality for studying early disease mechanisms and conducting effective preclinical drug screening. To
address these limitations, we propose a zebrafish-based model system. Zebrafish offer rapid development,
optical transparency, genetic tractability, and high fecundity, making them ideal for high-throughput compound
screening. Importantly, they share conserved myelination and neuroendocrine pathways with humans, making
them well-suited for modeling 4H. Using CRISPR-Cas9 genome editing and morpholino-based gene interference,
we will generate and validate zebrafish models deficient in polr3a, polr3b, or polr3k. These models will provide
the first in vivo platform for systematically investigating early POLR3-associated pathology and facilitating the
discovery of therapeutic compounds. Our multidisciplinary team brings extensive expertise in zebrafish modeling,
gene editing, transcriptomics, and neurodegenerative disease research, supported by state-of-the-art facilities
for in vivo imaging and high-throughput screening. This project will deliver essential tools and insights to
accelerate the development of effective therapies for 4H leukodystrophy.

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