An international team of researchers has successfully regenerated spinal tissue in rat models using a new gene therapy designed to break down scar tissue and allow new nerve cells to grow. The therapy, which used a common antibiotic as the on/off switch to activate the treatment for two months, resulted in rats with spinal injuries relearning complex hand movements.

Despite a number of exciting advances in the field of spinal injury regeneration over recent years, there is still no treatment available to help those that have damaged spinal cords regain simple control over things like hand movement. One of the big challenges in overcoming this problem is that following a traumatic spinal injury there tends to be an accumulation of scar tissue that prevents nerve cells from regenerating and reconnecting.

For some years scientists have known that the direct administration of an enzyme called chondroitinase can promote nerve recovery by breaking down that scar tissue. Several animal trials have shown this enzyme to be effective in restarting new nerve growth, but the need for repeated, and invasive, administration has slowed the research into a human clinical treatment.

More recent work has revealed a potential gene therapy solution, optimizing the release of chondroitinase by increasing the expression of the gene that triggers its production. Of course, the subsequent problem faced by researchers is that simply over-expressing a certain gene in an uncontrolled way can result in problematic off-target side effects. So, any effective gene therapy needs to be temporally controllable.

This latest discovery by a team led by researchers at King's College London allows the gene therapy to be easily switched on and off via the administration of a common antibiotic.

"What is exciting about our approach is that we can precisely control how long the therapy is delivered by using a gene 'switch'," explains Elizabeth Bradbury, from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King's College. "This means we can hone in on the optimal amount of time needed for recovery. Gene therapy provides a way of treating large areas of the spinal cord with only one injection, and with the switch we can now turn the gene off when it is no longer needed."

One of the clever strategies the team developed to make this new therapy successful is adding a so-called "stealth gene" to the treatment. Previous studies that scaled up the gene therapy in primate models revealed that an immune system response generally activated against the artificial gene switch mechanism. To overcome this immune response the researchers hid the mechanism in a "stealth gene" that can effectively avoid detection from immune activated T-cells.

"The use of a stealth gene switch provides an important safeguard and is an encouraging step toward an effective gene therapy for spinal cord injury," says Joost Verhaagen, from the Netherlands Institute for Neuroscience. "This is the first time a gene therapy with a stealth on/off switch has been shown to work in animals."

In experiments with rats that had spinal injuries designed to mimic those of humans after traumatic impacts, the researchers found the gene therapy was effectively switched on and off through the administration of doxycycline. After two and a half weeks an improvement was seen in simple ladder walking tests, and after eight weeks of treatment there were significant increases in skilled hand function.

"Rats and humans use a similar sequence of coordinated movements when reaching and grasping for objects," explains Emily Burnside from the IoPPN. "We found that when the gene therapy was switched on for two months the rats were able to accurately reach and grasp sugar pellets. We 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."

At this stage, the treatment still needs further development before it moves to human trials. The safeguard on/off switch was not 100 percent effective in these early experiments with a small amount of the artificially administered gene found to remain active even when it wasn't switched on by the activating antibiotic. Further research is necessary to entirely shut down the gene's activity before larger trials can be started.

The research was published in the journal Brain.

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