Bakken, K. | bioRxiv Science

bioRxiv2026

In Vivo Selection of anti-glioblastoma DNA aptamer-drug conjugates in an orthotopic patient-derived xenograft model

Glioblastoma (GBM) is an aggressive, high-grade glioma with a near-universally fatal prognosis. Therapeutic failure is often attributed to the highly selective blood brain barrier (BBB), the diffuse infiltrative nature of the tumor, and the marked intratumoral heterogeneity of GBM. Although antibody drug conjugates ADCs have shown promise for high grade gliomas such as GBM, efficacy is limited by ADC size. Aptamers--short, synthetic, single-stranded DNA or RNA molecules--can be [~]6-fold lower in molecular weight than IgG antibodies and have the potential to cross the intact BBB. Unlike other nucleic acid-based therapies, aptamer function arises from three-dimensional shape rather than genetic coding. Here we aim to replace the targeting component of the ADC paradigm with a DNA aptamer, thus creating an aptamer-drug conjugate (ApDC). We employed in vivo SELEX using an orthotopic patient-derived xenograft (PDX) GBM mouse model and a vast ([~]100 trillion 80-mer sequences) ApDC library. We report the results from this first in vivo ApDC selection of its kind. We characterize target tissue binding ex vivo, cell association, biodistribution, and pharmacokinetics from this selection. This study exemplifies an unbiased approach to a problem that rational design has yet to overcome, offering a new direction for GBM therapeutic development.

cancer biology↗

bioRxiv2024

Corticospinal excitability at rest outside of a task does not differ from task intertrial intervals in healthy adults

Human corticospinal excitability modulates during movement, when muscles are active, but also at rest, when muscles are not active. These changes in resting motor system excitability can be transient or longer lasting. Evidence from transcranial magnetic stimulation (TMS) studies suggests even relatively short periods of motor learning on the order of minutes can have lasting effects on resting corticospinal excitability. Whether individuals are able to return corticospinal excitability to out-of-task resting levels during the intertrial intervals of behavioral tasks that do not include an intended motor learning component is an important question. Here, in twenty-six healthy young adults, we used single-pulse TMS and electromyography (EMG) to measure motor evoked potentials (MEPs) during two different resting contexts: 1) intertrial intervals of a choice-reaction time task, and 2) outside the task. In both contexts, five TMS intensities were used to evaluate possible differences in recruitment of corticospinal output. We hypothesized resting state excitability would be greater during intertrial intervals than out-of-task rest, reflected in larger MEP amplitudes. Contrary to our hypothesis, we observed no significant difference in MEP amplitudes between out-of-task rest and in-task intertrial intervals, and instead found evidence of equivalence, indicating that humans are able to return to a stable motor resting state within seconds after a response. These data support the interpretation that rest is a uniform motor state in the healthy nervous system. In the future, our data may be a useful reference for motor disorder populations with an impaired ability to return to rest.

neuroscience↗