Reversable Acute Sedation Response of Phosphorothioate Antisense Oligonucleotides Following Local Delivery to the Central Nervous System

O'Rourke, J. G.; Bachmann, G.; Mazur, C.; Zhou, K.; Platoshyn, O.; Hernandez, M. B.; Klein, S.; Nguyen, J.; Burel, S.; Hoffmaster, C.; Zanardi, T.; Jafar-nejad, P.; Marsala, M.; Henry, S. P.; Swayze, E. E.; Powers, B.; Kordasiewicz, H. B.

doi:10.1101/2025.02.13.638136

bioRxiv · 10.1101/2025.02.13.638136

Reversable Acute Sedation Response of Phosphorothioate Antisense Oligonucleotides Following Local Delivery to the Central Nervous System

O'Rourke, J. G.·Bachmann, G.·Mazur, C.·Zhou, K.·Platoshyn, O.·Hernandez, M. B.·Klein, S.·Nguyen, J.·Burel, S.·Hoffmaster, C.·Zanardi, T.·Jafar-nejad, P.·Marsala, M.·Henry, S. P.·Swayze, E. E.·Powers, B.·Kordasiewicz, H. B.

View original source ↗Export metadata ↓

Abstract

Antisense oligonucleotides (ASOs) locally delivered to the central nervous system (CNS) are being approved as therapies for neurological diseases. After intrathecal injection of some ASOs, transient toxicities have been reported, but considerable inconsistencies remain in classifying them and their underlying mechanisms. Here, we characterize an acute sedation response that can include loss of lower spinal reflexes, hypoactivity, paresis, sedation and ataxia, peaking [~]3 hours post-intrathecal injection of some phosphorothioate ASOs and reversing by 24 hours with no sequelae. Acute sedation is distinct from acute activation, which is hyperactivity and muscle cramping that occurs immediately after administering oligonucleotides. Acute sedation translates across species from rodents to non-human primates and is sequence-, dose-, and chemistry-dependent. Acute sedation can be mitigated by strategic placement of phosphorothioate backbone linkages in ASOs and by avoiding G-rich sequences. The acute sedation response can be modeled in primary neural cultures, with good predictability of in vivo response. Mechanistically, we demonstrate that acute sedation is caused by high extracellular ASO concentrations inhibiting synaptic transmission, which reverses as ASO is cleared from the extracellular space and taken up into cells. Our results provide a comprehensive framework for quantifying and mitigating acute sedation caused by some phosphorothioate ASOs. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/638136v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@c3c957org.highwire.dtl.DTLVardef@1d7a062org.highwire.dtl.DTLVardef@162adf5org.highwire.dtl.DTLVardef@18ad055_HPS_FORMAT_FIGEXP M_FIG C_FIG

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

O'Rourke, J. G., Bachmann, G., Mazur, C., Zhou, K., Platoshyn, O., Hernandez, M. B., Klein, S., Nguyen, J., Burel, S., Hoffmaster, C., Zanardi, T., Jafar-nejad, P., Marsala, M., Henry, S. P., Swayze, E. E., Powers, B., Kordasiewicz, H. B.. 2025-02-17. Reversable Acute Sedation Response of Phosphorothioate Antisense Oligonucleotides Following Local Delivery to the Central Nervous System. https://doi.org/10.1101/2025.02.13.638136

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

CoReg, tracking-based motion compensation for in vivo calcium imaging

In vivo calcium imaging enables the observation of neural activity with high spatial and temporal resolution. However, recordings are frequently affected by motion artifacts caused by animal movement, physiological processes, tissue drift, or instability of the imaging setup. These artifacts make signal extraction harder and reduce the consistency of downstream analyses. Current registration methods can correct rigid and non-rigid motion, but often estimate motion from individual frames or image patches and make limited use of temporal information. In addition, activity-driven fluorescence changes can make it difficult to distinguish changes in image appearance from actual motion. Here, we treat motion correction in calcium imaging as a point tracking problem and introduce CoReg, an open-source Python- based software tool with a graphical user interface. We benchmark CoReg against established registration methods using fluorescence imaging datasets from multiple species. CoReg performs competitively with or better than existing approaches across several settings. We further show that its performance is robust to the choice of tracked points, making the method straightforward to apply. CoReg includes implementations of both our method and the evaluated established methods. Our results show that tracking-based registration provides a simple and reliable approach for motion correction in vivo calcium imaging.

neuroscience↗

bioRxiv2026

A shared slowing axis and phenotype-specific rhythms link clinical EEG to FDG-PET dementia phenotypes

Early and accurate identification of neurodegenerative disorders has notable implications for treatment and quality of life. Whereas neuroimaging-based biomarkers can accurately identify neurodegenerative subtypes, EEG represents a low-cost alternative that could expand access to dementia care. Here, we investigated whether six data-driven EEG latent factors, derived by nonnegative tensor decomposition of clinical EEGs, differ systematically across FDG-PET-defined neurodegenerative phenotypes. In 455 patients with EEG and FDG-PET acquired within one year of each other, factor expression was compared across 14 diagnostic classes assigned by StateViewer, a validated artificial intelligence framework for FDG-PET interpretation. To separate disease-general severity from phenotype-specific topography, each factor was also regressed on a subject-level slowing index. Finally, we related the factors to regional FDG uptake and to neuropsychological performance (n = 98) and assessed their potential utility for single-subject classification. Four factors reflecting neurophysiological oscillations (posterior alpha, Rolandic beta, frontotemporal delta-theta and posterior theta-slow alpha) varied significantly across phenotypes, with attenuation of faster and augmentation of slower rhythms most pronounced in dementia with Lewy bodies (DLB), dysexecutive Alzheimer disease (AD) and posterior cortical atrophy, whereas factors dominated by eye-movement and muscle artifact showed no robust phenotypic association. Alpha and beta effects were largely attributable to overall slowing, whereas posterior theta-slow alpha became more phenotype-specific after adjustment (eta-squared 0.082 to 0.147), dissociating the Alzheimer disease spectrum from frontotemporal syndromes. The slowing index tracked with an FDG-PET pattern highly associated with DLB across the cohort, irrespective of assigned phenotype (r = 0.51, P < 0.001). Consistent with a model in which dementia phenotypes reflect altered hippocampal-neocortical oscillatory coupling (stochastic latent oscillatory diffusion), frontotemporal delta-theta tracked a limbocortical axis of metabolic pattern expression, rising with neocortical and falling with limbic-predominant involvement, independent of overall slowing and phenotype. Each factor mapped onto a distinct metabolic topography, with frontotemporal delta-theta resembling Alzheimer-type hypometabolism and posterior theta-slow alpha the medial occipital hypometabolism of DLB. In terms of neuropsychological performance, Rolandic beta was associated with executive functions, and frontotemporal delta-theta with memory, visuospatial and global performance. Using these four factors alone, an exploratory logistic regression classifier separated cognitively unimpaired participants from DLB, posterior cortical atrophy, typical AD, and dysexecutive AD (area under the curve > 0.8) but poorly discriminated frontotemporal dementia phenotypes canonically associated with 4-repeat tau. Thus, data-driven decomposition of clinical EEG separates oscillatory activity from artifact into factors that track metabolic phenotype, regional metabolism and cognition, capturing both overall slowing and phenotype-specific patterns. This work informs the further development of scalable, biology-informed EEG-based phenotyping of neurodegenerative disease.

neuroscience↗

bioRxiv2026

An application of fNIRS for the prediction of hearing thresholds in sleeping infants: a proof of principle

This study applied a two-component-response modelling approach to fNIRS recordings obtained from naturally sleeping infants presented with auditory stimuli at different sound intensities. We investigated whether the relationship between fNIRS response measures and stimulus intensity could be modelled to estimate individual auditory hearing thresholds. In the normal-hearing group, 75% of infants had threshold estimates for the sound /ba/ within the expected normal-hearing range, with an estimated mean equivalent normal loudness (ENL) of 10.72 dB HL (SD 8.64 dB HL). A case study further explored the potential application of this approach in an infant with hearing impairment, highlighting the importance of reliable responses at lower stimulus intensities and appropriate regression model selection. These findings provide preliminary evidence that cortical haemodynamic responses can be quantitatively related to sound intensity for estimating auditory sensitivity.

neuroscience↗