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Calcium: A Key Player for a Promising and Safe Brain Treatment?

Calcium is a chemical element with the symbol Ca and atomic number 20. It is an essential nutrient required by the human body for building and maintaining strong bones and teeth, as well as for many other important functions, including nerve function, muscle contraction, and blood clotting.

Scientists at Tokyo Medical and Dental University (TMDU) have discovered that the side effects associated with treating brain disorders using antisense oligonucleotides are linked to changes in calcium balance.

A potential treatment for various brain disorders involves the use of antisense oligonucleotides (ASOs)—unique molecules capable of regulating RNARibonucleic acid (RNA) is a polymeric molecule similar to DNA that is essential in various biological roles in coding, decoding, regulation and expression of genes. Both are nucleic acids, but unlike DNA, RNA is single-stranded. An RNA strand has a backbone made of alternating sugar (ribose) and phosphate groups. Attached to each sugar is one of four bases—adenine (A), uracil (U), cytosine (C), or guanine (G). Different types of RNA exist in the cell: messenger RNA (mRNA), ribosomal RNA (rRNA), and transfer RNA (tRNA).” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>RNA and modifying protein synthesis—by directly administering them into the cerebrospinal fluid surrounding the brain and spinal cord. However, this method of injection frequently leads to significant side effects.

In a recent study published in the journal Molecular Therapy—Nucleic Acids, scientists from Japan have discovered that the adverse effects associated with antisense oligonucleotide therapy are due to imbalances in brain calcium levels. They also found that these side effects can be mitigated by using modulators that help regulate calcium balance.

Many brain diseases are thought to be caused by specific proteins. ASOs can be created to bind to the 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, which flows in and around the whole brain and spinal cord. However, only one such ASO treatment is currently available, to treat spinal muscular atrophy.

Antisense oligonucleotides for treatments of neurological diseases, directly injected into cerebrospinal fluid in spaces around the brain, may cause side effects, abnormalities of consciousness or motor function. These side effects can be predicted by calcium decrease in neuronal cells. Credit: Department of Neurology and Neurological Science, TMDU

Many other promising ASOs can induce neurotoxicity (that is, they cause disturbances of consciousness or motor function), which is experienced as unpleasant and sometimes life-threatening side effects. Because the reason for this neurotoxicity is relatively unknown, treating ASO-related neurotoxicity or creating new ASOs with low neurotoxicity is difficult. The researchers from Tokyo Medical and Dental University (TMDU) wanted to address this problem.

“We used three different ASOs that we know are neurotoxic and injected them into the cerebrospinal fluid of mice,” says lead author Chunyan Jia. “The mice showed many abnormal behaviors that indicated acute neurotoxicity, and these behaviors were correlated with changes in calcium levels, as measured in other experiments with neuronal cells.”

Specifically, when the neurotoxic ASOs were used to treat cells, they reduced the levels of free calcium within the cells. Importantly, these reductions were associated with neurotoxicity levels in the mice. The results indicated that calcium levels within cells are important for modulating ASO neurotoxicity, and suggested ways of modifying the calcium balance to reduce neurotoxicity.

“Our findings have important implications for developing effective ASO therapies with fewer harmful side effects,” explains Kotaro Yoshioka, senior author.

“As well as suggesting drugs that may be used alongside ASOs to reduce neurotoxicity, we also reported a relationship between certain nucleotide sequences in ASOs and greater neurotoxicity; this information may be useful when choosing potential ASOs for clinical use,” says Takanori Yokota, director of the research group.

Given that many neurological diseases have no cure or effective treatment, the development of new therapeutic agents is very important. The findings of this study will pave the way for more ASO-based therapies with fewer side effects, and are also expected to improve the ASO development pipeline for very rare brain diseases.

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

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.

Source: SciTechDaily