Pioneer SCA Translational Research Grants

Harry Orr, PhD
University of Minnesota, Minneapolis, MN

Towards an ASO Therapy for Spinocerebellar Ataxia Type 1
Spinocerebellar ataxia type 1 (SCA1) is a fatal inherited form of ataxia that currently has no effective treatment. Studies using mouse models of SCA1 have shown that reducing expression of the SCA1 gene can reduce SCA1-like symptoms, including dysfunction in movement and premature death. Our team’s research has shown that SCA1 gene expression can be reduced with a drug called an antisense oligonucleotide (ASO). In mice who have SCA1, treatment with an ASO relieved SCA1-like symptoms. Assessing whether therapies are effective in slowing neurodegeneration is difficult using only clinical scales because SCA1 progresses slowly in the body, and it presents in many different ways. Thus, development of additional ways to follow progress of SCA1 might speed moving a drug to clinical trials. To do this, we will use magnetic resonance spectroscopy neuroimaging to examine the brains of the mice before and after they receive the ASO therapy. Our hope is that our research will inform a future pathway for bringing effective ASO therapy to patients with SCA1.

Patrícia Maciel, PhD
University of Minho, Braga, Portugal

Testing the therapeutic potential of Mesenchymal Stem Cells and their secretome in an animal model of spinocerebellar ataxia type 3

Mesenchymal stem cells are cells that come from several tissues, including bone marrow. Research has revealed that these types of cells have a great potential to regenerate damaged organs and tissues. As a result, they are being tested as biological therapy agents against neurodegenerative diseases. Although the effect of the cells has been studied in several neurodegenerative diseases—including ataxias—with promising results, no pre-clinical studies have been done for spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD).

The goal of this project to study the effectiveness of using either mesenchymal stem cells or biological products derived from these cells to treat SCA3/MJD. For this research, we will evaluate the short-term and long-term effect of these treatments on mice that have SCA3/MJD and have impairments in movement. The tests will measure balance, strength and movement coordination. About 6 months after the stem cells or their biological products have been given to the mice, we will also look at the effectiveness of the treatment in reducing the death of neurons in different areas of the mice’s nervous system. Finally, we will compare different protocols, including different injection sites, to determine which one has a higher effect. In total, the findings of this research should provide important proof-of-concept information for future clinical studies of mesenchymal stem cells in patients with SCA3/MJD.

Willeke M.C. van Roon-Mom, PhD
Leiden University Medical Center, The Netherlands

Advancing the therapeutic potential of exon skipping for Spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3) is a hereditary form of ataxia where the area of the brain called the cerebellum is most affected. SCA3 is caused by over repetition of CAG sequences in a specific region of the DNA. In healthy individuals, up to 51 repeats of CAG appear, but in people with SCA3, the CAG repeats increase to 51 times or more. Ataxin-3 is an important protein in the brain but becomes toxic with this over repetition of repeats.

My team’s research has shown that we can remove specifically the region of the ataxin-3 protein that contains the over repetition by using molecules called antisense oligonucleotides (AONs). In doing so, we are able to directly remove the cause of SCA3 without reducing the amount of ataxin-3 protein. Maintaining ataxin-3 protein levels in the body is key because ataxin-3 seems to be an important protein for normal brain function. When testing the treatment in mice, use of the AONs was well tolerated and effective. To bring the treatment closer to use in patients, we will be further testing the AONs to find the ones that best targets the cause of the SCA3. We will also be testing cultured cells to determine that it is safe to use in humans.