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Assessment of Intrathecal Delivery of MaCPNS1 as an Effective Technique for Localized Transduction of Dorsal Root Ganglia in Rats
Stein, Anna-Lena
Stein, Anna-Lena
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2025-05
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Bioengineering
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https://doi.org/10.34944/m0xg-vg44
Abstract
MaCPNS1, an AAV capsid variant, efficiently transduces the peripheral nervous system in rodents via intravenous tail vein injections with robust transduction of dorsal root ganglia (DRG) across all vertebral levels. This could make it an important tool for spinal cord injury research, where transducing DRGs is important in the study of neuromodulation therapies. However, transduction across all vertebral levels could affect critical physiological functions, such as breathing, once the transduced neurons are activated by clozapine N-oxide (CNO). For spinal cord injury rehabilitation specifically, a key refinement would be to restrict the expression to the lumbar spinal cord to avoid unintended activation of thoracic or cervical afferents that might disrupt critical physiological functions. Currently, targeted delivery to the peripheral nervous system via direct surgical injection is challenging and time-consuming, taking up to several hours per animal. Intrathecal injection for DRG transduction as an alternative to current methods could accelerate research in spinal cord injury and neurological diseases significantly. This study aims to determine whether intrathecal delivery of MaCPNS1 can selectively transduce lumbar DRGs and therefore could be used as an effective alternative to direct DRG injection surgeries. The transduction efficiency of MaCPNS1 in locally transducing DRG through intrathecal delivery at L3-L4 was assessed, followed by an analysis of differences in walking gait at different speeds before and after activation of MaCPNS1 transduced afferents with CNO. Histological data revealed significant differences in transduction efficiency across lumbar, thoracic, and cervical regions, with lumbar DRGs showing the strongest transduction. Additionally, kinematic data support the hypothesis that lower to moderate speeds are more sensitive to DREADD activation, with feedback from sensory afferents amplifying gait variability, while still offering opportunities for enhancement of data reliability and accuracy. These findings suggest that while work remains to optimize the yield rate of the surgical delivery method, intrathecal delivery of MaCPNS1 may potentially offer a more precise and less invasive alternative to traditional methods, accelerating research into spinal cord injury.
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