You Must Chase-It

Posted by Sam Maddox in Research News on November 14, 2015 # Research

Chase-ItTurns out CHASE-IT stands Chondroitinase ABC for Spinal Injury Therapy. It’s a collaborative project between four lab groups, led by: Elizabeth Bradbury (King’s College London), Elizabeth Muir (University of Cambridge), Joost Verhaagen (Netherlands Institute for Neuroscience), and Rafael Yáñez-Muñoz (Royal Holloway, University of London).

I knew Spinal Research had made a major commitment to moving the scar-buster drug chondroitinase ABC, nicknamed chase, toward human trials. I didn’t know until now that they had developed a catchy brand called CHASE-IT and a logo (hat tip to the annual research review newsletter from NeuroKinex, a not-for-profit activity-based rehab program in London, Belfast and Bristol, UK). SR has raised about half a million dollars so far toward Chasing It.

Says SR:
“... the members are working together to reduce the clinical concerns surrounding a gene delivery system for chondroitinase treatment and to optimize a proposed safety system for effective clinical delivery of the gene. Specifically, the teams are working to reduce toxicity, remove the chance of tumor formation and contain the treatment to the target tissue. They have chosen to focus on two different delivery systems to transport chondroitinase to the injury site in animal models of spinal cord injury. Both delivery systems are similar in concept and work in broadly the same way by making use of a virus as a vehicle to carry a therapeutic gene into cells which then go on to produce the therapeutic protein chondroitinase.

Here’s more about what that statement is all about.

As you know if you follow SCI research, chase has been an intriguing potential therapy for a number of years. We’ve looked at it many times, here and here and just a few weeks ago, here.

Quick review: injured axons, or nerve fibers, in the spinal cord try to mount a regenerative response. They are stuck, however, in a thick scar tissue that has sealed off the area of damage. To get unstuck, chase, an enzyme which is derived from a toxic bacteria, can be applied to dissolve the scar. This works great in controlled experiments, but getting chase to the right place in a living animal, and keeping the drug active at body temperature – that has not been so easy.

One of the ways scientists have devised to supply the scar-buster where it’s needed is to genetically engineer a sort of molecular Trojan horse -- in the form of a virus that delivers gene codes for chase to cells in the area of the stuck axons; this turns on production of chase on the spot. Can this really work? Yes, apparently quite nicely in animal models for both thoracic and cervical contusion injury models, as reported by the Elizabeth Bradbury lab, a pillar of the CHASE-IT campaign.

Bradbury’s latest paper, from September, is titled “Chondroitinase gene therapy improves upper limb function following cervical contusion injury.” This follows up on previous work in her lab showing that chase via viral vector significantly improved function in a thoracic contusion model of SCI in lab animals.

From the paper:

We recently demonstrated that delivery of mammalian-compatible ChABC via gene therapy led to sustained and widespread digestion of CSPGs, resulting in significant functional repair of a moderate thoracic contusion injury in adult rats. Here we demonstrate that chondroitinase gene therapy [using a lentiviral vector to deliver a modified mammalian-compatible ChABC gene to the adult mammalian spinal cord] results in endogenous expression of active enzyme] significantly enhances upper limb function following cervical contusion injury, with improved forelimb ladder performance and grip strength as well as increased spinal conduction through the injury site and reduced lesion pathology.

That chondroitinase gene therapy has now been shown to be efficacious in contusion models at either thoracic or cervical level is an important step in the further development of this promising therapeutic strategy towards the clinic.

These results indicate that LV-ChABC leads to significant improvements in both upper and lower limb functions following a cervical contusion injury.

Efficacy of chondroitinase gene therapy treatment has now been demonstrated in clinically relevant contusion injury models at both thoracic and cervical levels. 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.

Bradbury, who has been funded by the Reeve Foundation, is eager to test the chase delivery system in bigger animals, and she’s quite optimistic about getting it to humans. CHASE-IT good.

With apologies to the band Devo, okay, and to Spinal Research:

Crack that whip
Give the past a slip
Step on a crack
Break your momma's back
When a problem comes along
You must CHASE IT.

Sorry, could not resist. Whip it good.

Samuel David Awarded
Kudos to Samuel David, winner November 13 of the $50,000 Barbara Turnbull prize in Toronto. This annual award is supported through a partnership between the Barbara Turnbull Foundation, Brain Canada, and the Canadian Institutes of Health Research (CIHR).

Turnbull was a journalist who was rendered quadriplegic in a 1982 shooting. She helped set up the awards to recognize those who raise awareness of spinal cord injury. Turnbull, who reported for the Toronto Star, died last May.

David, a scientist at the Research Institute of the McGill University Health Centre, is best known by the SCI research world as co-author of a seminal series of papers in the early 1980s; he was a young post-doc in the Albert Aguayo lab when they successfully regenerated central nerves in peripheral nerve grafts, thus setting the stage for a major shift in the direction of SCI research. This work also set hope in motion; it now seemed that repair of the injured spinal cord might be possible.

The announcement took place during the 14th Annual Charles H. Tator-Barbara Turnbull Lectureship Series in Spinal Cord Injury.

The National Paralysis Resource Center website is supported by the Administration for Community Living (ACL), U.S. Department of Health and Human Services (HHS) as part of a financial assistance award totaling $8,700,000 with 100 percent funding by ACL/HHS. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by ACL/HHS, or the U.S. Government.