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

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT ALBANY · 2024 · $32,057

## Abstract

Project Summary
Microsatellite expansions cause over 50 neurodegenerative and neuromuscular diseases, with CAG repeat
expansions being one of the most common classes of disease-causing repeats. CAG repeat expansion
diseases, which include Huntington’s disease (HD), spinal and bulbar muscular atrophy (SBMA), and
spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7 and 12, share the production of CAG expansion RNAs and in
most cases, the expression of toxic polyglutamine containing proteins. Despite these shared features, there are
no cross-disease therapeutic approaches and there is a lack a clear understanding of the precise molecular
mechanisms responsible for disease pathogenesis. While current therapeutic approaches focus mostly on
treating symptoms, there are multiple available targets in the pathogenic cascade for these diseases: the CAG
expansion containing gene, expansion transcripts, and/or expansion proteins. Therapeutic approaches in
preclinical development that target this cascade have been largely gene-specific, offering hope for one disease
but not for the larger family of CAG repeat diseases. Our approach of designing therapeutic strategies that
selectively target abundance of CAG RNAs has the potential to alleviate the underlying mechanisms and impact
all downstream aspects of the pathogenic cascade across multiple CAG repeat expansion diseases. Our central
hypothesis for the parent grant is that targeting CAG expansions with small molecules will provide therapeutic
efficacy across multiple CAG SCAs. To this end, we have already identified multiple small molecules that
selectively reduce levels of CAG transcripts across SCA1, SCA3 and SCA7 patient-derived fibroblasts and SCA1
mice providing proof-of-concept for a cross-disease small molecule approach for CAG expansion SCAs. In the
parent grant, we will leverage our established pipeline to identify FDA-approved small molecules and natural
products with therapeutic efficacy across CAG SCAs. This supplement is focused on complementary studies to
investigate the therapeutic potential of our lead candidate small molecules in Huntington’s disease models and
in combination with protein regulating small molecules. By expanding the group of diseases for our novel, RNA
targeting small molecules, Daphne will gain valuable training experience while providing key information as to
whether CAG repeat selective compounds could provide therapeutic benefit beyond the SCAs. Furthermore,
while compounds that target SCA proteins, most notably ATXN3, and the huntingtin protein have been published,
the possibility of an additive effect of small molecules that target both protein and RNA has yet to be considered
for CAG expansion diseases. Therefore, Daphne’s investigation of combination therapeutics for CAG SCAs and
the broader group of CAG expansion diseases has the potential to uncover promising strategies that maximize
therapeutic benefit whilst minimizing off target effects of any individual small molec...

## Key facts

- **NIH application ID:** 11034540
- **Project number:** 3R01NS135254-01S1
- **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:** $32,057
- **Award type:** 3
- **Project period:** 2024-06-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11034540

## Citation

> US National Institutes of Health, RePORTER application 11034540, Alternative Splicing and Development of Small Molecule Therapeutics in CAG Expansion Spinocerebellar Ataxias (3R01NS135254-01S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11034540. Licensed CC0.

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