by Summary: The side effects of treating neurological disorders with antisense oligonucleotides (ASOs) are caused by calcium imbalances in the brain. Such side effects can be improved by using calcium balance modulators.
Source: Tokyo University of Medicine and Dentistry
A promising therapy for a range of brain disorders involves antisense oligonucleotides (ASOs) – specialized molecules that can modulate RNA and alter protein production – injected directly into the cerebrospinal fluid in the space around the brain and spinal cord. Unfortunately, when ASOs are injected this way, they often cause severe side effects.
In a recent study published in Molecular Therapy – Nucleic Acids, Japanese researchers showed that such side effects are caused by calcium imbalances in the brain and can be improved by calcium balance modulators.
Many brain diseases are believed to be caused by specific proteins. ASOs can be designed to bind to the RNA that provides a template for a disease-related protein, usually with the goal of making more or less of the protein.
To alter protein production only in the brain, ASOs are then injected directly into the patients’ cerebrospinal fluid, which flows in and around the entire 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 (that is, they cause impaired consciousness or motor dysfunction), which are perceived as unpleasant and sometimes life-threatening side effects. Since the reason for this neurotoxicity is relatively unknown, treating ASO-related neurotoxicity or creating new ASOs with low neurotoxicity is difficult.
The researchers at the Tokyo Medical and Dental University (TMDU) wanted to tackle this problem.
“We used three different ASOs that we know to be neurotoxic and injected them into the cerebrospinal fluid of mice,” says lead author Chunyan Jia.
“The mice displayed many abnormal behaviors indicative of acute neurotoxicity, and these behaviors correlated with changes in calcium levels as measured in other neuronal cell experiments.”
In particular, when the neurotoxic ASOs were used to treat cells, they reduced the levels of free calcium in the cells. Importantly, these reductions were associated with neurotoxicity levels in the mice.
Results showed that cellular calcium levels are important for modulation of ASO neurotoxicity and suggested ways to modify calcium balance to reduce neurotoxicity.
“Our results have important implications for developing effective ASO therapies with fewer harmful side effects,” said Kotaro Yoshioka, senior author.
“Not only have we proposed drugs that can be used with ASOs to reduce neurotoxicity, but we have also reported a relationship between specific nucleotide sequences in ASOs and greater neurotoxicity; this information can be helpful in selecting potential ASOs for clinical use,” says Takanori Yokota, director of the research group.
Since there is no cure or effective treatment for many neurological diseases, the development of new therapeutics is very important. The results 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.
About this news from neurology research
Author: Kotaro Yoshioka
Source: Tokyo University of Medicine and Dentistry
Contact: Kotaro Yoshioka – Tokyo Medical and Dental University
Picture: The image is in the public domain
Original research: Open access.
“Change in intracellular calcium levels causes acute neurotoxicity by antisense oligonucleotides via the CSF pathway” by Takanori Yokota et al. Molecular Therapy – Nucleic Acids
Abstract
Alteration of intracellular calcium levels causes acute neurotoxicity by antisense oligonucleotides via the CSF pathway
Antisense oligonucleotides (ASOs) are promising therapeutics for intractable central nervous system (CNS) disorders. For this clinical application, neurotoxicity is one of the critical limitations.
Therefore, an assessment of this neurotoxicity from a behavioral perspective is important to reveal symptomatic CNS dysfunction and elucidate the underlying molecular mechanism.
Here, we used a behavioral analysis method to categorize and quantify the acute neurotoxicity of mice administered toxic ASOs via intracerebroventricular injection.
The toxic ASOs were found to reduce consciousness and locomotor function in mice in a dose-dependent manner. Mechanistically, we analyzed the effects of modulators targeting receptors or channels that regulate calcium influx from neurons on ASO neurotoxicity.
Modulators that promote calcium influx were decreased while those that inhibited calcium influx increased, in vivo Neurotoxicity of ASOs in mice. in a (n in vitro Assay to determine intracellular free calcium concentrations using rat primary cortical neurons, toxic ASOs reduced calcium concentrations.
The results of this study revealed the behavioral characteristics of ASO-induced neurotoxicity and indicated that changes in intracellular free calcium levels are part of the mechanism underlying the neurotoxic effects of ASO.
