Immune-evasive gene switch enables regulated delivery of chondroitinase after spinal cord injury

摘要: Chondroitinase ABC is a promising preclinical therapy that promotes functional neuroplasticity after CNS injury by degrading extracellular matrix inhibitors. Efficient delivery of chondroitinase to the injured mammalian spinal cord can be achieved viral vector transgene delivery. This approach dramatically modulates pathology and restores sensorimotor functions. However, clinical development this limited lack ability exert control over gene expression. Prior experimental regulation platforms are likely incompatible with non-resolving adaptive immune response known occur following injury. Therefore, here we apply novel immune-evasive dual system, in which under doxycycline inducible regulatory switch, utilizing chimeric transactivator designed evade T cell recognition. Using demonstrate tight temporal expression, effectively removing treatment upon removal doxycycline. enables comparison short long-term paradigms clinically-relevant cervical level contusion injuries adult rats. We reveal transient (2.5 weeks) sufficient promote improvement sensory axon conduction ladder walking performance. tasks requiring skilled reaching grasping, only long term (8 leads significantly improved function, rats able accurately grasp retrieve sugar pellets. The late emergence hand function indicates enhanced connectivity correlates increased density vGlut1‰+ innervation grey matter, particularly lamina III–IV above below Thus, our system provides an tool study effects digestion as well encouraging step towards generating safer strategy, longer administration increases recovery descending motor control. could have significant impact for tetraplegic individuals, whom important determinant independence, supports ongoing application