Summary of A Key Player for a Promising and Safe Brain Treatment?:
Tokyo Medical and Dental University (TMDU) scientists have linked imbalances in brain calcium levels to the side effects linked to treatment of brain disorders using antisense oligonucleotides (ASOs). ASOs are used to regulate RNA and modify protein synthesis and are used in potential treatments for various brain disorders, however the direct injection into cerebrospinal fluid frequently leads to significant side effects. ASOs can be created to bind to RNA that provides a template for a disease-related protein, usually with the aim of making more or less of the protein; to alter protein production in the brain only, ASOs are then injected directly into patients’ cerebrospinal fluid. By injecting three ASOs that the researchers knew were neurotoxic into the cerebrospinal fluid of mice, they found that the mice showed many abnormal behaviours that indicated acute neurotoxicity which were correlated with changes in calcium levels. The results showed the importance of calcium levels within cells for modulating ASO neurotoxicity, and suggested ways of modifying the calcium balance to reduce neurotoxicity.
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Calcium Imbalances Linked to Side Effects of Antisense Oligonucleotide Therapy
Antisense oligonucleotides (ASOs) are being looked at as viable treatments for various brain disorders. These molecules can regulate RNA by directly introducing them into the cerebrospinal fluid surrounding the brain and spinal cord. However, this approach can be associated with severe side effects. Thus, scientists from Tokyo Medical and Dental University (TMDU) set out to study these side effects and have discovered that calcium imbalances are linked to the adverse reactions.
Understanding Antisense Oligonucleotide
ASOs have been engineered to bind to RNA that is responsible for specific proteins in the brain that contribute to brain diseases. These ASOs can be administered directly into the cerebrospinal fluid to alter protein production in the brain, therefore, treating brain diseases.
The ASO Method for Treating Brain Disorders
Currently, just one ASO treatment is available for spinal muscular atrophy. However, ASOs still hold potential in being an effective treatment for various brain disorders. When administering ASOs, their neurotoxicity can lead to severe side effects. Neurotoxicity, caused by ASOs, leads to disturbances of consciousness or motor function.
Calcium Imbalance and Neurotoxicity
Scientists have discovered that calcium levels play a crucial role in modulating ASO neurotoxicity. When ASOs were used to treat cells, they reduced the levels of free calcium, which was associated with neurotoxicity in mice. Side effects can, therefore, be reduced by regulating calcium balance.
ASOs for Rare Brain Diseases
The findings of this study pave the way for ASO-based therapies with fewer side effects. Also, the ASO development pipeline for very rare brain diseases is expected to improve. The implications of this study include suggestions for drugs that can be used with ASOs to reduce neurotoxicity.
A Ray of Hope
Given that many neurological diseases have no cure or effective treatment, these findings are promising as new therapeutic agents are very important. This critical investigation now opens the door for more ASO-based therapies that address various neurological issues with fewer adverse side effects, thus offering patients a ray of hope.
Reference: “Change of intracellular calcium level causes acute neurotoxicity by antisense oligonucleotides via CSF route” by Chunyan Jia, Su Su Lei Mon, Ying Yang, Maho Katsuyama, Kie Yoshida-Tanaka, Tetsuya Nagata, Kotaro Yoshioka and Takanori Yokota, 23 December 2022, Molecular Therapy – Nucleic Acids.
DOI: 10.1016/j.omtn.2022.12.010
Funding: The study was funded by the Japan Agency for Medical Research and Development, the Japan Science and Technology Agency, and the Japan Society for the Promotion of Science.
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