Researchers Awarded More Than $2.9 Million to Explore Treatments for Spinocerebellar Ataxias

By Erin Frick 

ALBANY, N.Y. (Jan. 23, 2024) — University at Albany researchers at the RNA Institute and scientists at Albany Medical College have received new funding to study and develop new drugs to treat spinocerebellar ataxias caused by CAG repeat expansion mutations. The five-year grant, totaling more than $2.9 million, was awarded by the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health.

Spinocerebellar ataxias are a type of neurodegenerative disease that disrupts muscle coordination and balance throughout the body due to cellular atrophy in the brain. Symptoms can include slurred speech, tremors, cognitive impairment, and diminished reflexes.

CAG repeat expansions are a type of cellular mutation caused by sections of the genetic code expanding when cells try to repair damage to their DNA or the cells divide during replication. These expansions lead to the production of toxic RNA and proteins and disrupt normal cell functioning. These types of mutations have been linked to over 50 different repeat expansion diseases including many different genetic forms of spinocerebellar ataxias.

“Our goal for this newly funded project is to identify existing FDA-approved small molecule therapeutics (drugs) that can be used to treat spinocerebellar ataxias caused by CAG repeat expansions,” said co-principal investigator Hannah Shorrock, a research scientist at the RNA Institute. “We will also examine the role of alternative splicing dysregulation — a newly identified molecular signature of CAG spinocerebellar ataxias — in disease onset and progression.”  

Additional co-principal investigators on the grant include UAlbany’s Andy Berglund, director of the RNA Institute and professor of biological studies, and Damian Shin, interim chair and associate professor in the Department of Neuroscience and Experimental Therapeutics at Albany Medical College.

Exploring alternative splicing dysregulation

Alternative splicing is a process that allows a single gene to be expressed, or “spliced” into different products. This mechanism allows for the production of the wide diversity of proteins from a single gene, a process that is needed to support complex lifeforms. Alternative splicing dysregulation is when abnormalities occur during this process, mixing up the ways in which the genes are spliced, which can cause disease.

The team’s proposed work will build on their recent study, published in the journal Brain, which examined alternative splicing dysregulation, focusing on genetic data collected from mice affected by CAG spinocerebellar ataxias (CAG SCAs). Co-authors included collaborators from the RNA Institute and UAlbany’s Department of Biological Sciences, as well as student researchers participating in the RNA Institute’s summer bioinformatics program.

“Developing new disease treatments requires a thorough understanding of the mechanisms that shape disease progression in the body,” said Berglund. “Because a direct link between alternative splicing dysregulation and disease symptoms has been well established in other repeat expansion diseases, most notably myotonic dystrophy, we wanted to know whether alternative splicing dysregulation contributes to disease onset in CAG SCAs, and whether dysregulation could represent an early signal of disease shared among multiple CAG SCAs, including spinocerebellar ataxias.”

In this study, the team analyzed the RNA sequences generated from affected brain regions of mice with CAG expansion SCAs. Across all the RNA datasets included in the study, the team examined alternative splicing to identify patterns in splicing anomalies across different SCAs caused by CAG repeat expansions.

“We found evidence of widespread alternative splicing dysregulation across affected brain regions in mice with CAG expansion SCAs,” Shorrock said. “We also found that this dysregulation affected genes that function in cellular pathways known to be disrupted in CAG SCAs, and that dysregulation occurred before symptoms appeared. These results indicate that alternative splicing dysregulation is a novel hallmark of CAG expansion SCAs and may represent a biomarker that can be used in preclinical therapeutic studies in these diseases.

“Because alternative splicing dysregulation is detectable before symptoms appear, if this is consistent with the patient disease, alternative splicing could be used to monitor the effectiveness of potential drugs in patients before symptoms appear.”

Next steps: Testing drugs against multiple repeat expansion diseases

In the next phase of this work, the team will screen FDA-approved drugs to assess their ability to reduce toxic RNAs and resulting harmful proteins in cells effected by CAG SCAs. Successful drugs will be tested in cell lines established from SCA patients before moving on to testing in mice. At each stage, the team will assess alternative splicing dysregulation to see if changes are responsive to the therapeutic candidate being tested.

“Using a transgenic animal model of Spinocerebellar Ataxia Type 1 (SCA1), my lab will work closely with the UAlbany scientists to test their screened-out small molecule candidates,” said Shin. “Through this continued collaboration between Albany Medical College and UAlbany, we hope to provide critical proof of concept data that these small molecules can serve as a therapeutic for this disease.”

“We are now aiming to identify drugs that can reduce expression of CAG repeat expansions across multiple different SCAs,” Shorrock said. This means that it is possible that if these drugs work across the eight different CAG SCAs, they also might work on other CAG repeat expansion diseases.

“While some of these diseases are heavily studied and well funded, others are extremely rare, understudied and do not receive a lot of research funding. The work funded by this grant could therefore benefit patients and inform disease pathology across a wide range of repeat expansion diseases, from the rare CAG expansion SCAs to myotonic dystrophy, Huntington’s disease and potentially a common form of ALS.”