# A whole body model of Pol III-related leukodystrophy

> **NIH NIH R21** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2021 · $462,000

## Abstract

Project Summary
RNA polymerase (Pol) III-related leukodystrophy is a recently identified autosomal recessive
neurodegenerative disorder that causes hypomyelination with variable disease onset and severity. The disease
is usually identified during childhood based on neurological deficits that include developmental delay, cognitive
regression, a progressive decline in motor function and intellectual disability. Additional clinical characteristics
can include myopia, hypodontia and endocrine abnormalities. An understanding of the disease mechanisms is
currently lacking and progress has been limited by the absence of an animal model. Recent work has
generated a lineage-specific knock-in mouse model of Pol III-related leukodystrophy that exhibits a subset of
disease features found in patients and a relatively mild disease course. However, this model lacks gross motor
defects and cerebellar phenotypes that are generally associated with more severe disease. Pol III-related
leukodystrophy patients express mutant Pol III subunits in all somatic cells yet the disease is predominantly
limited to the central nervous system. Thus, to better model the human disease, a conditional whole-body
knock-in mouse was developed. This mouse model exhibits gross motor defects and a more severe disease
course. The goals of this proposal are to characterize behavioral and neuropathological phenotypes of these
mice and to profile Pol III transcriptional changes in neural cell populations to develop a molecular
understanding of disease pathogenesis. In addition, we will test a genetic strategy for suppression of
transcriptional and disease phenotypes. These studies will significantly enhance understanding of the
pathogenesis of Pol III-related leukodystrophy and will provide a whole-body model system for testing
therapeutic approaches targeting the disease.

## Key facts

- **NIH application ID:** 10287751
- **Project number:** 1R21NS123730-01
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Robyn Moir
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $462,000
- **Award type:** 1
- **Project period:** 2021-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10287751

## Citation

> US National Institutes of Health, RePORTER application 10287751, A whole body model of Pol III-related leukodystrophy (1R21NS123730-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10287751. Licensed CC0.

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