summary: A side effect of treatment of neurological disorders with antisense oligonucleotides (ASOs) is caused by a calcium imbalance in the brain. These side effects can be ameliorated with the use of calcium balancing agents.
sauce: Tokyo Medical and Dental University
Antisense oligonucleotides (ASOs)—specialized molecules that can modulate RNA and alter protein production—are injected into the cerebrospinal fluid in the space surrounding the brain and spinal cord as a potential therapy for a variety of brain diseases. It involves injecting directly into Unfortunately, injecting ASOs in this way often causes serious side effects.
In a recent study published in Molecular Therapy-Nucleic Acids, Japanese researchers revealed that such side effects are caused by an imbalance of calcium in the brain and can be ameliorated by calcium balance regulators.
Many brain diseases are believed to be caused by specific proteins. ASOs can be engineered to bind to RNAs that provide templates for disease-associated proteins, usually with the goal of making more or less proteins.
To alter protein production in the brain only, ASOs are injected directly into the patient’s cerebrospinal fluid and flow throughout and around the brain and spinal cord. However, only one such ASO treatment is currently available to treat spinal muscular atrophy.
Many other promising ASOs can induce neurotoxicity (ie, cause impairment of consciousness or motor function) and are experienced as unpleasant and sometimes life-threatening side effects. The reason for this neurotoxicity is relatively unknown, making it difficult to treat ASO-related neurotoxicity or to create new ASOs with less neurotoxicity.
Researchers at Tokyo Medical and Dental University (TMDU) wanted to tackle this problem.
“We used three different ASOs that are known to be neurotoxic and injected them into the cerebrospinal fluid of mice,” says first author Chunyan Jia.
“The mice exhibited many abnormal behaviors indicative of acute neurotoxicity. These behaviors correlated with changes in calcium levels, as measured in other experiments with neurons. ”
Specifically, the use of neurotoxic ASOs to treat cells reduced the level of intracellular free calcium. Importantly, these decreases were associated with neurotoxicity levels in mice.
The results indicated that intracellular calcium levels are important for regulating ASO neurotoxicity and suggested ways to modify calcium balance to reduce neurotoxicity.
“Our findings have important implications for developing effective ASO therapies with fewer adverse side effects,” explains lead author Kotaro Yoshioka.
“We not only suggested drugs that could be used in combination with ASOs to reduce neurotoxicity, but also reported the relationship between specific nucleotide sequences of ASOs and greater neurotoxicity. It may be helpful in selecting potential ASOs,” says Takanori Yokota, director of the research group.
Given the lack of cures or effective treatments for many neurological diseases, the development of new therapeutic agents is of great importance. The findings of this study are also expected to pave the way for more ASO-based treatments with fewer side effects and improve the ASO development pipeline for very rare brain diseases.
About this Neurology Research News
author: Kotaro Yoshioka
sauce: Tokyo Medical and Dental University
contact: Kotaro Yoshioka – Tokyo Medical and Dental University
image: image is public domain
Original research: open access.
“Alteration of intracellular calcium levels triggers acute neurotoxicity by antisense oligonucleotides through the CSF pathwayTakanori Yokota et al. Molecular therapy — nucleic acids
overview
Alteration of intracellular calcium levels triggers acute neurotoxicity by antisense oligonucleotides through the CSF pathway
Antisense oligonucleotides (ASOs) are promising therapeutics for intractable central nervous system (CNS) diseases. Neurotoxicity is one of the significant limitations in this clinical application.
Evaluating this neurotoxicity from a behavioral perspective is therefore important for clarifying symptomatic dysfunction in the central nervous system and for elucidating the underlying molecular mechanisms.
Here, we utilized behavioral analysis methods to classify and quantify acute neurotoxicity in mice administered toxic ASOs via intracerebroventricular injection.
Toxic ASO was found to reduce consciousness and locomotor function in mice in a dose-dependent manner. bottom.
modulators that promote calcium influx are moderated, those that inhibit calcium influx are increased, in vivo ASO neurotoxicity in mice.and in vitro In an assay evaluating intracellular free calcium levels using rat primary cortical neurons, toxic ASOs reduced calcium levels.
The findings of this study demonstrate the behavioral properties of ASO-induced neurotoxicity and reveal that changes in intracellular free calcium levels are part of the mechanism underlying ASO’s neurotoxic effects.
