# Alternative Splicing and Development of Small Molecule Therapeutics in CAG Expansion Spinocerebellar Ataxias

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT ALBANY · 2024 · $24,542

## Abstract

Project Abstract
Microsatellite repeat expansions are a growing family of 50+ neurological, neuromuscular, and
neurodegenerative diseases that includes the most common cause of adult-onset muscular dystrophy (myotonic
dystrophy, DM) and large group of rare neurodegenerative diseases spinocerebellar ataxias, SCAs). There are
more than 40 genetically heterogeneous rare SCAs, with the most common forms associated with CAG repeat
expansion mutations. Expression of these repeats leads to translation into toxic polyglutamine expansion
proteins whose pathogenic role is not well understood. The Berglund and Shorrock groups have preliminary data
that supports alternative splicing as a novel CAG-dependent transcriptomic hallmark of SCAs and that targeting
CAG repeat expansions with small molecules could provide therapeutic potential across multiple SCAs. The
focus of this supplement for Caroline Pritchard is a parallel study that seeks to draw potential overlaps in the
transcriptomic dysregulation in CAG SCAs and another repeat expansion disease, myotonic dystrophy type 1
(DM1). In contrast to the SCAs, the mechanism of disease pathogenesis for DM1 is well studied and involves
the expression of CUG expansion RNAs that sequester RNA binding proteins, leading to alternative splicing
dysregulation and a “spliceopathy”. This project, which supports the research and career training of Caroline
Pritchard, will focus on bioinformatic approaches to characterize the interface between these repeat expansion
disorders. The overlap in transcriptomic dysregulation between brains affected by CAG SCAs and CUG DM1 is
expected to reveal underlying common disease pathomechanisms, which will complement the parent grant’s
focus on CAG SCA disease mechanisms. Furthermore, the project will explore if splicing dysregulation
associated with repeat expansion diseases is coordinated at the transcript level by long-read sequencing
technologies. By characterizing parallel alternative splicing disease mechanisms in multiple repeat expansion
disease and the synergy in splicing dysregulation at the transcript level will not only enhance our understanding
of the disease biology of SCAs but also open up new potential avenues for therapeutic development across the
entire family of repeat expansion diseases.

## Key facts

- **NIH application ID:** 11089895
- **Project number:** 3R01NS135254-01S2
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT ALBANY
- **Principal Investigator:** Andrew Berglund
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $24,542
- **Award type:** 3
- **Project period:** 2024-09-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11089895

## Citation

> US National Institutes of Health, RePORTER application 11089895, Alternative Splicing and Development of Small Molecule Therapeutics in CAG Expansion Spinocerebellar Ataxias (3R01NS135254-01S2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11089895. Licensed CC0.

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