Chondroitinase ABC: Gene therapy giving hope to spinal injury patients.

Gene Therapy

It is a promising technique for disease treatment, in which genetically modified cells are transferred into or generated within individuals for therapeutic purpose. The cells with modified genes can be induced to differentiate into desired cell types or produce proteins needed for tissue repair. There are two strategies that are currently used in gene therapy, viral transduction and non-viral transfection, and both strategies can be conducted in vivo and ex vivoIn vivo gene therapy is simple but often lacks controlled tracking of the gene-modified cells and target site specificity. An attractive alternative is to combine gene therapy with tissue-engineering approaches to transduce or transfect cells of interest ex vivo and then use a carrier or scaffold to deliver these genetically modified cells to the target site. This approach offers the advantages of flexibility of target cell type and retainment of gene-modified cells at the site of interest. Gene transduction using viral vectors, such as retrovirus, adenovirus, and lentivirus, effectively modifies the host chromosome but raises concerns about mutagenesis and possible immune reactions. In contrast, a non-viral approach is safer but the efficiency of transduction is lower.

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Chondroitinase ABC for Neural Regeneration Research

Chondroitin sulphate proteoglycans (CSPGs) are known to be important contributors to the intensely inhibitory environment that prevents tissue repair and regeneration following spinal cord injury. The bacterial enzyme chondroitinase ABC (ChABC) degrades these inhibitory molecules and has repeatedly been shown to promote functional recovery in a number of spinal cord injury models.

The CSPG inhibitors include core proteins (aggrecan, neurocan, versican and NG2) with a sulfated glycosaminoglycan (GAG) side chain. The GAG side chain is a major factor that is responsible for blocking axon regrowth. However, by treating the blocked axon site with a chondroitinase ABC enzyme the CSPGs can be degraded. This enzyme catalyzed reaction removes GAG side chains and as a result there is some recovery of the spinal cord. This mechanism shows promise for work in in vivo and in vitro models of CNS damage repair, disc degeneration and low back pain, with hopes to ultimately lead to new treatments and therapies for patients.

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Chondroitinase ABC: Gene therapy giving hope to spinal injury patients

People with spinal cord injury often lose the ability to perform everyday actions that require coordinated hand movements. The researchers tested a new gene therapy for regenerating damaged tissue in the spinal cord that could be switched on and off. After a traumatic spinal injury, dense scar tissue forms which prevents new connections being made between nerve cells. The gene therapy causes cells to produce an enzyme called chondroitinase which can break down the scar tissue and allow networks of nerve cells to regenerate.

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Researchers have demonstrated a novel immune-evasive gene switch that enables regulated delivery of ChABC in the injured mammalian spinal cord. This provides an experimental tool to control delivery (by effectively switching the gene on and off) and understand the role of timing in ChABC treatment, as well as a step towards creating a clinically applicable viral vector system.

Rats and humans use a similar sequence of coordinated movements when reaching and grasping for objects. Researchers found that when the gene therapy was switched on for two months the rats were able to accurately reach and grasp sugar pellets. They also found a dramatic increase in activity in the spinal cord of the rats, suggesting that new connections had been made in the networks of nerve cells.

The researchers had to overcome a problem with the immune system recognizing and removing the gene switch mechanism. To get around this, the researchers added a ‘stealth gene’ which hides the gene switch from the immune system.

Prof Elizabeth Bradbury told the BBC: “We find this really exciting, recovery of this type of function, because for spinal injured patients their highest priority is to get their hand function back.

This gene therapy is not yet ready for human trials. While the ability to switch a therapeutic gene off provides a safeguard, the researchers found a small amount of the gene remained active even when switched off. They are now working on shutting the gene down completely and moving towards trials in larger species.

It will now be important to determine if similar effects are observed in larger animal models and if its efficacy can be further enhanced by combination with additional therapeutic strategies. These findings show promise for the further development of chondroitinase gene therapy, as well as other strategies which target CSPGs, as potential therapeutics for restoring function following spinal cord injury.

Burnside et al. Immune-evasive gene switch enables regulated delivery of chondroitinase after spinal cord injury. Brain, 2018.

©BforBiotech by Bedadyuti Mohanty, Assistant Managing Editor by Profession and Bio-technologist by heart.

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