Noninvasive Focal Gene Delivery of Functional Neural Actuators to the Primate Spinal Cord using Focused Ultrasound
Pathologies of the spinal cord -- from degenerative diseases to chronic pain -- represent a substantial global health burden. Although surgical and pharmacological treatments for spinal cord pathologies have advanced considerably, therapies capable of addressing the cellular mechanisms underlying these conditions remain limited. Viral gene therapies present a compelling alternative, allowing for…
Spinal cord disorders, including degenerative diseases and chronic pain, pose a significant global health burden. Current therapies, both surgical and pharmacological, have limitations in addressing the cellular mechanisms behind these conditions. Viral gene therapies hold promise as they can deliver therapeutic genes directly to specific cell types involved in these pathological processes.
The challenge lies in finding a noninvasive and focal method to deliver these gene therapies across the restrictive vascular boundaries of the blood-spinal cord barrier (BSCB). Researchers have now demonstrated a method that achieves this goal using focused ultrasound (FUS) in marmoset nonhuman primates.
Through a systematic exploration of various ultrasonic pressures and central frequencies, the researchers determined the optimal set of FUS parameters for effective, spatially targeted molecular delivery across the marmoset BSCB. With these parameters in place, they successfully utilized FUS to create a disruption in the BSCB, allowing for the focal penetration of systemically administered viral vectors.
These vectors were capable of transducing both fluorescent transgenes and excitatory chemogenetics within the targeted spinal segments of the marmosets.
To confirm the functional impact of this gene delivery method, the researchers employed positron emission tomography (PET) imaging. The PET scans revealed a significant increase in metabolic demand within the targeted area of the spinal cord following chemogenetic actuation, providing evidence of functional transgene expression in vivo.
Behavioral and histopathological assessments further demonstrated that FUS BSCB disruption and viral delivery did not compromise neurological function or tissue integrity, indicating a safe approach for noninvasive delivery of receptor-based gene therapies in marmosets.
To ensure the broad applicability of this platform, the research team generated an ultra-high-resolution (74 m) multimodal MRI/CT spinal cord template. This template facilitates precise targeting and anatomical localization during the delivery of receptor-based gene therapeutics in marmosets. Additionally, the researchers have made the engineering drawings and CAD files for their M-FRAME system (Marmoset Fixation and Reorientation Apparatus for Multimodal Experiments) available as open-access resources.
These resources enable precise and repeatable spinal targeting without the need for surgical fixation. By establishing the safety and efficacy of FUS-mediated BSCB disruption for noninvasive, focal gene delivery to the primate spinal cord, this study opens up new possibilities for the treatment of spinal cord pathologies.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
