Summary: Side effects of treating neurological disorders with antisense oligonucleotides (ASO) are caused by calcium imbalances in the brain. These side effects may be improved by the use of calcium balance modulators.
Source: Tokyo Medical and Dental University
A promising therapy for a range of brain diseases involves antisense oligonucleotides (ASOs) – specialized molecules that can modulate RNA and alter protein production – directly injected into the cerebrospinal fluid, the space around the brain and of the spinal cord. Unfortunately, when ASOs are injected in this way, they often cause serious side effects.
In a recent study published in Molecular Therapy—Nucleic Acids, Japanese researchers revealed that these side effects are caused by calcium imbalances in the brain and can be improved by calcium balance modulators.
Many brain diseases are thought to be caused by specific proteins. ASOs can be created to bind to RNA that provides a template for a disease-related protein, usually with the goal of making more or less protein.
To alter protein production in the brain alone, ASOs are then injected directly into patients’ cerebrospinal fluid, which circulates in and around the entire brain and spinal cord. However, only one ASO treatment of this type is currently available, to treat spinal muscular atrophy.
Many other promising ASOs can induce neurotoxicity (ie they cause disturbances in consciousness or motor function), which are experienced as unpleasant and sometimes fatal side effects. Since the reason for this neurotoxicity is relatively unknown, it is difficult to treat ASO-related neurotoxicity or to create new ASOs with low neurotoxicity.
Researchers from the Tokyo Medical and Dental University (TMDU) wanted to solve 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 exhibited numerous 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 neurotoxic ASOs were used to treat cells, they reduced free calcium levels in cells. Importantly, these reductions were associated with levels of neurotoxicity in mice.
The results indicated that calcium levels in cells are important in modulating ASO neurotoxicity and suggested ways to alter calcium balance to reduce neurotoxicity.
“Our findings have important implications for the development of effective ASO therapies with fewer harmful side effects,” says lead author Kotaro Yoshioka.
“In addition to suggesting drugs that can be used with ASOs to reduce neurotoxicity, we have also reported a relationship between certain nucleotide sequences in ASOs and greater neurotoxicity; this information may be helpful when choosing potential ASOs for clinical use. says Takanori Yokota, director of the research group.
Since many neurological diseases have no cure or effective treatment, the development of new therapeutic agents is very important. The results of this study will pave the way for more ASO-based therapies with fewer side effects, and should also improve the ASO development pipeline for very rare brain diseases.
About this neurology research news
Author: Kotaro Yoshioka
Source: Tokyo Medical and Dental University
Contact: Kotaro Yoshioka – Tokyo Medical and Dental University
Picture: Image is in public domain
Original research: Free access.
“Change in intracellular calcium level causes acute neurotoxicity by antisense oligonucleotides via CSF pathway” by Takanori Yokota et al. Molecular Therapy — Nucleic Acids
Abstract
Change in intracellular calcium level causes acute neurotoxicity by antisense oligonucleotides via CSF pathway
Antisense oligonucleotides (ASOs) are promising therapeutic agents for refractory diseases of the central nervous system (CNS). For this clinical application, neurotoxicity is one of the critical limits.
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 exploited a behavioral analysis method to categorize and quantify the acute neurotoxicity of mice administered with toxic ASOs by intracerebroventricular injection.
Toxic ASOs were found to reduce consciousness and locomotor function in mice in a dose-dependent manner. Mechanistically, we analyzed the effects of modulators against receptors or channels, which regulate calcium influx from neurons, on ASO neurotoxicity.
Modulators favoring calcium influx attenuated, while those hindering calcium influx increased, live ASO neurotoxicity in mice. In a in vitro To assess intracellular free calcium levels using primary rat cortical neurons, toxic ASOs reduced calcium levels.
The results of this study demonstrated the behavioral characteristics of ASO-induced neurotoxicity and revealed that changes in intracellular free calcium levels are part of the mechanism underlying the neurotoxic effects of ASO.