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Quantifying and mitigating motor phenotypes induced by antisense oligonucleotides in the central nervous system
Michael P Moazami1, Julia M Rembetsy-Brown1, Samantha L Sarli1
1RNA Therapeutics Institute, UMass Chan Medical School, Worcester, MA 01605 USA.
Summary
Antisense oligonucleotides (ASOs) can treat neurological diseases but may cause motor side effects. Modifications to ASO chemistry and formulation can improve their safety and tolerability in the central nervous system (CNS).
Area of Science:
- Neuroscience
- Oligonucleotide Therapeutics
- Toxicology
Background:
- Antisense oligonucleotides (ASOs) show promise for treating neurological disorders via cerebrospinal fluid injection.
- Phosphorothioate (PS)-modified gapmer ASOs can induce transient motor deficits, including ataxia and seizures, following CNS administration.
- Understanding and mitigating ASO-induced neurotoxicity is crucial for advancing these therapeutics.
Purpose of the Study:
- To investigate the impact of ASO chemical modifications and formulation on acute motor phenotypes after CNS delivery.
- To elucidate the mechanisms underlying ASO-induced neurotoxicity.
- To identify strategies for improving the tolerability of ASO therapeutics in the central nervous system.
Main Methods:
- Development of a specialized behavioral scoring assay to quantify ASO-induced motor effects.
- Systematic evaluation of various sugar and phosphate modifications on ASO tolerability.
- Assessment of the role of PS content and formulation strategies (divalent ions, buffer choice) in ASO toxicity.
- Investigation of potential involvement of nucleic acid sensing immune pathways.
Main Results:
- Both sugar and phosphate modifications significantly influence ASO-induced motor phenotypes; 2'-substituted RNA modifications enhance tolerability compared to DNA.
- Reducing the phosphorothioate (PS) content of gapmer ASOs improves their toxicity profile, though sometimes at the cost of efficacy or duration.
- Acute ASO toxicity is not primarily mediated by major nucleic acid sensing immune pathways.
- Formulation with divalent ions and avoidance of phosphate buffers offer modest improvements in ASO tolerability.
Conclusions:
- ASO chemical structure and formulation critically impact central nervous system (CNS) tolerability.
- Platform-level medicinal chemistry and formulation approaches can mitigate ASO-induced neurotoxicity.
- This study provides valuable insights into oligonucleotide toxicology in the CNS, paving the way for safer ASO therapeutics.
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