# Modulating Lamin B1 levels  as a therapeutic strategy for Autosomal Dominant Leukodystrophy

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $228,465

## Abstract

Abstract
 Autosomal Dominant Leukodystrophy (ADLD) is a fatal, progressive adult-onset disease characterized by
autonomic and motor dysfunction with widespread CNS demyelination. We have previously shown that ADLD is
caused by duplications of the lamin b1 gene and that increased expression of lamin B1 underlies the disease
process. In eukaryotic cells, lamin B1 is a major constituent of the nuclear lamina, a fibrous meshwork adjacent
to the inner nuclear membrane. We have demonstrated that transgenic (TG) mice with oligodendrocyte specific
over-expression of lamin B1 exhibit severe vacuolar demyelination of the spinal cord that result in age dependent
degenerative phenotypes that recapitulate the salient features of ADLD.
 The late age of onset of the together with the relatively slow progression of the disease provides a large
therapeutic window for the disorder. However, no treatment exits for ADLD, representing an urgent and unmet
clinical need. This proposal aims to test the hypothesis that reducing lamin B1 levels can delay or reverse the
progression of the disease in a a novel mouse model we have generated where the overexpression of Lamin B1
can be inducibly downregulated. We propose to fully characterize this mouse model and downregulate
overexpression at time points before and after the onset of disease to determine if this will mitigate the
pathological phenotype. These experiments will provide the first clear evidence that reducing Lamin B1 levels is
a viable therapeutic strategy in an ADLD pre-clinical model.

## Key facts

- **NIH application ID:** 10788444
- **Project number:** 5R21NS131906-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Quasar S Padiath
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $228,465
- **Award type:** 5
- **Project period:** 2023-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10788444

## Citation

> US National Institutes of Health, RePORTER application 10788444, Modulating Lamin B1 levels  as a therapeutic strategy for Autosomal Dominant Leukodystrophy (5R21NS131906-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10788444. Licensed CC0.

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