Chondroitinase ABC (Ch’ase) a potential future deal maker for Spinal Cord Injuries

Inhibition by scar tissue
Following injury, specialised glial cells that normally support neurons accumulate at the injury site and deposit scar tissue.

Scar tissue is a major obstacle to spinal cord repair because it creates a physical and biochemical blockage that neurons must grow through. Perhaps more importantly, molecules that inhibit neuronal growth are especially concentrated in the scar.

Scientists have now identified the main inhibitory component of scar tissue. In the laboratory an enzyme called chondroitinase ABC has been shown to dissolve away vital parts of these inhibitors and stop their effects.

In 2002, scientists showed that injecting chondroitinase ABC into the injury site every other day for 10 days, starting immediately after injury, destroyed important molecules in the scar known as CSPGs in the damaged area and enabled some of the damaged neurons to regrow across the injured region. Neuronal growth of up to 4mm has been measured experimentally, accompanied by encouraging increases in sensation and muscle coordination.

Optimisation of engineered chondroitinase for treatment of spinal cord injury in humans

Dr Elizabeth Muir, Professors Roger Keynes and James Fawcett (Cambridge Centre for Brain Repair)
Bacterial chondroitinase has proven successful as a treatment for acute spinal cord injury and recently for chronic spinal cord injury, both in experimental animals. This robustness of efficacy makes it a very strong candidate for treatment of human spinal cord injury. However, since repeated injections are likely to be necessary, increasing the risk of further trauma and infection, and also of triggering a host immune response, its native form requires modification. We have recently engineered the bacterial chondroitinase cDNA so that it can be expressed as an active enzyme by mammalian cells. For treating human spinal cord injury we propose to engineer the transgene further to produce a form of chondroitinase that is non-immunogenic. In addition we will design an AAV vector for enzyme delivery to the site of injury. This will incorporate an on/off switch for regulated chondroitinase expression in the patient.

Chondroitinase treatment becomes research focus
A group of leading spinal cord repair researchers is coming together to formulate plans towards clinical trials using a very promising therapy – chondroitinase. When we awarded our first Translational Initiative grants in 2010, our aim was to identify leading clinical trial candidates amongst potential treatments for spinal cord injury (SCI) and fund the essential studies needed to achieve milestones that brought these potential treatments to a point where they are ready for studies on patients. The case for funding translational work around chondroitinase – a bacterial protein known to break down the injury scar tissue which represents a significant obstacle to repair – was already strong: the evidence supporting chondroitinase as a leading therapeutic candidate has built over a number of years, in numerous injury models and from many different laboratories around the world.

Chondroitinase therapy can enable injured nerves to regenerate through injury scar tissue and it may encourage “sprouting” of uninjured nerves into damaged areas where they may “take over” the role of the nerves that were damaged or lost. Researchers have also shown that chondroitinase gene therapy leads to widespread and sustained digestion of inhibitory molecules in the spinal cord. Nevertheless, issues remain surrounding potential concerns about repeated delivery of a bacterial enzyme to the delicate human spinal cord. Work being carried out by our Cambridge group, led by Dr Elizabeth Muir and Professors Roger Keynes and James Fawcett, is now overcoming many of these issues and the results are proving very exciting.

Confidence amongst leaders in the field surrounding this approach is now such that we have decided to pull together a panel of experts with the specific objective of establishing detailed plans for a final push to the clinic. The panel includes members with expertise in gene therapy, in vivo models of SCI, regulatory experience and clinical trial design: all the appropriate expertise and experience to plan and scope the work needed to achieve our aim.

During 2012 the group will deliver detailed development plans and a timetable of activities and supporting budgets for this important work to be carried out.
http://www.spinal-research.org/research/chondroitinase-becomes-research-focus/

A NEWLY RELEASED INTERACTIVE PRESENTATION OF THE POTENTIAL WITH NERVE GRAFTING AND CHONDROITINASE ABC (ch’ase).

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