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Abstract Chondroitinase ABC is a promising preclinical therapy that promotes functional neuroplasticity after CNS injury by degrading extracellular matrix inhibitors. Efficient delivery of chondroitinase ABC to the injured mammalian spinal cord can be achieved by viral vector transgene delivery. This approach dramatically modulates injury pathology and restores sensorimotor functions. However, clinical development of this therapy is limited by a lack of ability to exert control over chondroitinase gene expression. Descargar gratis libros. Prior experimental gene regulation platforms are likely to be incompatible with the non-resolving adaptive immune response known to occur following spinal cord injury.

Therefore, here we apply a novel immune-evasive dual vector system, in which the chondroitinase gene is under a doxycycline inducible regulatory switch, utilizing a chimeric transactivator designed to evade T cell recognition. Using this novel vector system, we demonstrate tight temporal control of chondroitinase ABC gene expression, effectively removing treatment upon removal of doxycycline. This enables a comparison of short and long-term gene therapy paradigms in the treatment of clinically-relevant cervical level contusion injuries in adult rats.

We reveal that transient treatment (2.5 weeks) is sufficient to promote improvement in sensory axon conduction and ladder walking performance. However, in tasks requiring skilled reaching and grasping, only long term treatment (8 weeks) leads to significantly improved function, with rats able to accurately grasp and retrieve sugar pellets. The late emergence of skilled hand function indicates enhanced neuroplasticity and connectivity and correlates with increased density of vGlut1+ innervation in spinal cord grey matter, particularly in lamina III–IV above and below the injury. Thus, our novel gene therapy system provides an experimental tool to study temporal effects of extracellular matrix digestion as well as an encouraging step towards generating a safer chondroitinase gene therapy strategy, longer term administration of which increases neuroplasticity and recovery of descending motor control. This preclinical study could have a significant impact for tetraplegic individuals, for whom recovery of hand function is an important determinant of independence, and supports the ongoing development of chondroitinase gene therapy towards clinical application for the treatment of spinal cord injury. ,, Introduction Spinal cord injury results in permanent disruption to nervous system function, for which there is no current regenerative or pathology-modifying treatment (). Following CNS injury, reactive glia synthesize and secrete chondroitin sulfate proteoglycans (CSPGs) into the extracellular matrix ().

CSPGs have one or more covalently attached chondroitin sulfate glycosaminoglycan (CS-GAG) side-chains, which are known to inhibit neuronal extension and plasticity. Removal of CS-GAGs by the chondroitinase ABC (ChABC) enzyme reverses neurite growth arrest in vitro (), enhances CNS axonal regeneration and neuroplasticity in vivo (; ) and promotes functional recovery following spinal cord injury in adult rats (; ). This effect has been replicated across multiple laboratories, species and CNS injury models (), and recently in a canine clinical trial (). A gene therapy method of enzyme delivery, where host cells are themselves transduced to express the ChABC gene, circumvents the need for repeated, invasive administration of the enzyme, which has low thermal stability () and a short half-life that is thought to limit efficacy in severe models of trauma that mimic clinical pathology (). We have previously reported a gene therapy strategy whereby optimization of the prokaryotic ChABC gene to render it compatible with translation and secretion from mammalian cells () and incorporation of this gene into viral vectors (), leads to high levels of ChABC gene expression and active enzyme release in vivo. This results in extensive CS-GAG digestion across many segments of the mammalian spinal cord ().

This large scale matrix modification leads to reduced tissue pathology and improved functional recovery following contusion injury to the thoracic () and cervical () spinal cord. Thus, ChABC gene therapy is a promising therapeutic strategy for the treatment of spinal cord injury. However, uncontrolled gene expression can limit or even reverse therapeutic benefits (; ).

Therefore, the ability to both administer and remove any treatment has a key advantage over permanent application in the development of clinically feasible strategies. Furthermore, most current clinical applications of gene therapy for treating human disorders are targeted mainly to rare genetic conditions with rapid progressive decline or fatal neurodegenerative diseases (), where any negative effects of gene delivery, which cannot be switched off, carry less risk in terms of cost-to-benefit analysis (). Spinal injured individuals, however, represent a higher risk group for irreversible gene therapy since they are a relatively stable population. Following the initial trauma, early surgical and medical interventions and a period of adjustment during which any spontaneous recovery reaches a plateau, the majority of spinal injured individuals remain in a stable condition for the rest of their lives, albeit severely debilitated (). Thus, an important safety consideration in the development of gene therapies for spinal cord injury and other long term neurological disorders is the ability to control transgene expression. Effective methods of regulating gene expression in the CNS would also expand the number of conditions that are amenable to gene therapy treatment. While there is no evidence that sustained ChABC gene therapy, at least for up to 12 weeks, has any negative effects in rats (), given its potent effects on neuroplasticity, the ability to switch off the gene represents a significant step towards generating a more clinically feasible treatment.