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bioRxiv · 10.1101/2024.09.11.612569

Harnessing Synaptic Vesicle Release and Recycling Mechanism for Molecule Delivery to Neurons

Yee, K. K.·Kumamoto, J.·Inomata, D.·Suzuki, N.·Harada, R.·Yumoto, N.
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Abstract

Neurodegenerative clinical trials often fail due to insufficient drug doses in reaching targeted cells and the unintended delivery to non-targeted cells. This study demonstrates an alternative neuron-selective drug delivery system, which utilizes the synaptic vesicle release and recycling mechanism (SVRM) by antibody shuttles targeting synaptic vesicle transmembrane proteins for molecule delivery. Using Synaptotagmin-2 (SYT2), we exemplify that intravenously administered anti-SYT2 antibodies localize to neuromuscular junctions, undergo uptake, and retrograde transport to ChAT-positive motor neurons (MNs) in the spinal cord and brainstem. The delivery of anti-microtubule agent and Malat1 gapmer antisense oligonucleotide to MNs with anti-SYT2 antibodies induces axon degeneration and reduction of Malat1 RNA expression, respectively. This approach circumvents the blood-spinal cord barrier, enabling selective delivery of therapeutic molecules to neurons while minimizing effects in non-targeted cells. Thus harnessing SVRM presents a promising strategy for enhancing drug concentrations in neurons and improving treatment efficacy for neurodegenerative diseases.

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Yee, K. K., Kumamoto, J., Inomata, D., Suzuki, N., Harada, R., Yumoto, N.. 2024-09-12. Harnessing Synaptic Vesicle Release and Recycling Mechanism for Molecule Delivery to Neurons. https://doi.org/10.1101/2024.09.11.612569

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