Scientists created a mouse model with the genetic change that causes DRPLA in people. These mice showed symptoms common of DRPLA, such as balance problems, seizures, tremors, and poor coordination. When the mice were treated with a type of genetic therapy called antisense oligonucleotides, researchers observed that the treatment protected them from many of these symptoms. Our partner organisation CureDRPLA funded this work and in this article we describe outcomes of this project led by Dr Jeff Carrol and his team at the University of Washington in collaboration with Ionis Pharmaceuticals, Inc.
DRPLA is caused by a genetic mutation in the Atrophin-1 (ATN1) gene. This gene contains a section where a short DNA sequence, made up of the letters C, A, and G, is repeated many times in a row. People with DRPLA have more than 48 repeats of the CAG sequence in the ATN1 gene. This makes the gene longer than normal, which affects how it makes proteins. These faulty proteins can harm cells and lead to symptoms.
Using genetic engineering, scientists inserted the human ATN1 gene into mice and they also introduced 112 CAG repeats so that the mice would develop DRPLA. These genetic changes caused the mice to present a severe form of DRPLA and started showing symptoms very early on. Researchers studied these mice in detail and used them to test possible treatments.
Antisense oligonucleotides (ASOs) have emerged as a promising strategy in various neurodegenerative disorders because they block the ability of a certain gene to make a protein. Researchers wanted to find out if giving ASO treatment, which is designed to lower levels of the harmful ATN1 gene message and protein, could help reduce DRPLA symptoms in mice and make a difference inside their cells.
DRPLA mice with 112 CAG repeats showed clear signs of poor coordination, tremors and sluggish behaviour. These issues were seen in mice that received no treatment. However, when the mice were treated with ASO during their first weeks of life, many of these symptoms improved significantly. The ASO-treated DRPLA mice moved more easily, were more active, froze less often and showed better overall neurological health. The treatment also helped improve their daily activity patterns, suggesting a broader benefit to their wellbeing.
Researchers looked at the brains of the DRPLA mice and found large amounts of abnormal protein buildup, called inclusions, in brain cells of untreated mice. These were seen in brain regions involved in movement, sensation and vision. The buildup found in brain cells was only present in the mice that received no treatment. In contrast, mice treated with ASO had very few of these inclusions, making their brain tissue look much more like that of mice with no DRPLA. This suggests that ASO treatment can greatly reduce the harmful protein buildup in the brain.
In this study, researchers created a mouse model of DRPLA and evaluated the effectiveness of ATN1 lowering using ASOs. The results showed that having 112 CAG repeats caused a severe form of DRPLA in the mice. When treated early in life, the mice showed strong improvements in their symptoms. However, it is important to note that the ASO treatment was given in the first few weeks of life, and it is unclear if later treatment would have had the same effect. The results of this study are encouraging and have helped motivate an ongoing clinical study to determine if ASOs could also help people living with DRPLA.
To read the full scientific article, visit this page.
