By Snigdha Kanadibhotla ‘21
Characterized by uncontrollable and spastic movements, Huntington’s Disease (HD) is a fatal neurodegenerative disorder that is estimated to affect about 1 in 10,000 people in the United States (1). HD has pervasive effects that damage neurons in brain regions associated with mobility, emotion, and intellectual capacity leading to symptoms such as depression, anxiety, and difficulty learning. Despite its complex and varied effects, the cause of HD is attributable to the mutation of a single gene. When key nucleotides of the HTT gene are mutated (known as a single nucleotide polymorphism or SNP), the resulting mutated form is denoted muHTT. muHTT toxically affects the expression of many other genes. Since muHTT has been identified as the prominent cause of HD, the focus of research into treatments for Huntington’s has been largely aimed at targeting the muHTT gene. One approach, called antisense oligonucleotides (ASOs), is capable of identifying and suppressing the muHTT gene and has come to the forefront of research. Previous studies involving animal models have shown that the use of ASOs are effective in minimizing the physical complications of HD. However, no research has been conducted in investigating the impacts of ASOs on the emotional and intellectual symptoms of HD.
In order to investigate these characteristics, a study conducted by Southwell et al. treated mice with HD using acute and chronic treatments of ASOs. First, behavioral tests were conducted that measured mice’s responsiveness when being left in open spaces as well as in drowning simulations. These two situations aimed to help researchers to understand how ASOs affected mice’s anxiety and depression, respectively. It was found that ASO-treated mice demonstrated significantly less anxiety and depression compared to controls. ASOs seemed to have a similar positive effect for the intellectual tests which showed that ASO-treated mice had better memory retention. Although the results from these two studies show that ASOs had an ameliorating effect, the optimal amount of ASO treatment differed between tests. The behavioral test showed that chronic treatments of ASO had more lasting effects on reducing anxiety while acute early treatments of ASO allowed for better long-term learning. The underlying mechanisms for these findings are currently unknown. Further investigation into how the rates of ASOs change in brain regions responsible for learning and emotions is critical before ASOs can be used in clinical experimentation on humans.
- S. Swierzewski, Huntington’s Disease. Health Communities (2000).
- A. Southwell, et. al., Huntingtin suppression restores cognitive function in a mouse model of Huntington’s disease. Science Translational Medicine 10, (461) (2018).
- Image retrieved from: https://en.wikipedia.org/wiki/Huntingtin#/media/File:PDB_3io4_EBI.png