SCIRF Progress Update – June 2017
1) Current Progress and Outcomes:
The Spinal Cord Injury Research Facility continues to make significant progress in a number of research areas with the goal of developing cures for spinal cord injury.
Connexin/Peptide project
Since we have now shown that peptide5 is effective for delivery via the blood stream as a treatment early after spinal cord injury, we now wish to test the efficacy of an existing drug (Tonabersat) that we have identified as a channel blocker. This drug has the real advantage in that it has already been used in several phase two clinical trials, including long term prophylactic use for migraine prevention, and is proposed as a treatment for epilepsy. It is therefore highly likely that we shall be able to move this drug to clinical trials much more quickly.
We now have evidence that connexin channels are involved in ongoing (chronic) inflammation after injury. This chronic inflammation leads to neuropathic pain and sustains an environment in the cord that does not promote nerve cell regrowth and reconnection. Therefore, we now plan to test Tonabersat as a treatment for chronic spinal cord injury. Reducing this inflammation will create an environment that decreases or prevents neuropathic pain and will increase the likely success of interventions such as our gene therapy approach. It will also allow for spontaneous regeneration of nerve cells leading to functional improvement.
We will be attempting to source funding from within New Zealand, in Australia with our collaborators at the University of New South Wales, and internationally in order to undertake this work.
Research testing modified Peptide 5 peptides, that may be more effective and/or more stable in the blood stream, is now complete. A Catwalk Trust funded summer student, Connor Clemett, (a Brain Bee SI winner from 2010) carried this work out over the 2016-2017 summer. We have found that 3 modified peptides appear to be more effective at closing channels than our native peptide. We plan to test these peptides in our spinal cord model as they have the potential as a more effective treatment for acute spinal cord injury. However, we are prioritising our work on Tonabersat as this drug has the potential to also be used for chronic injury and based on previous clinical use, can be moved to the clinic more rapidly.
The MRI experiments to observe the effect of the peptide on spinal cord swelling are ongoing. These experiments will be completed early next year as originally planned.
Gene therapy
This project, evaluating the use of gene therapy to deliver a protein that breaks down scar tissue after injury and allows for regrowth and reconnection of nerve cells has seen the completion of the first set of experiments testing delivery of the scar busting protein. Analysis of the data from this first study is almost complete and appears to show that we are able to break down the scar, allow nerve cells to regrow, reduce the size of the injury and improve hind limb function following injury. The fact that our treatment reduces injury size is very exciting as it shows that we are able to protect the tissue after injury and encourage nerve cell regrowth, allowing for the reconnection of nerve cells. From mid 2017 we will repeat these experiments using our gene therapy approach alongside intensive exercise training to facilitate the reconnection of nerve cells in the correct way and thus improve the functionall outcomes we have already seen with gene therapy alone. Future plans include the use of Tonabersat alongside gene therapy and exercise training. It is known that chronic inflammation restricts nerve regrowth. If results from these studies confirm that Tonabersat is able to reduce chronic inflammation then the proposed combination will enhance the ability for nerve cells to regrow and reconnect effectively, greatly improving the potential for functional recovery.
Antioxidants
Our previous studies have demonstrated that measuring the level of antioxidants in the cord after injury allows us to determine the extent of damage to the spinal cord. This is a very significant finding as it will extremely useful in developing treatments and advancing clinical trials for spinal cord injury. It will allow identification of precisely which patients are likely to respond to treatment and which treatment is likely to be best for each individual patient. We aim to test our peptide and other drug treatments so we can correlate the improvement seen following peptide/drug treatment with antioxidant levels.
2) New projects:
1) Protecting blood vessels
Following spinal cord injury blood vessels in the cord are damaged and become leaky. This allows blood to get into the cord and this makes the size of the injury larger. Following injury the blood vessels can remain leaky for as long as two weeks. Developing ways to protect the blood vessels and stop the leakiness are potential targets that will reduce the size of the injury. Three Honours student projects are currently underway in the lab to 1) understand specific changes that occur to blood vessels after injury that can be targeted with drugs; 2) test drugs that will potentially strengthen the blood vessels themselves and 3) test drugs that will help repair the damaged vessels and prevent the leakiness. These projects will be completed by the end of this year (2017) and the results will give us a much better understanding of how blood vessels are affected after injury and provide valuable information about a number of potential new drug treatments for spinal cord injury.
A goal of the SCIRF is to continue to develop new ideas and collaborations in order to identify potential treatmets for spinal cord injury. As described in the previous report (December 2016.), we have recently developed new collaborations that we believe have real potential.
2) Use of multielectrode arrays for guidance of nerve cells
A collaboration has been established with Dr Darren Svirkis (School of Pharmacy, University of Auckland) and Dr Maria Asplund (Freiburg Institute for Advanced Studies, Germany) to test the use of multielectrode arrays to guide the growth of nerve cells across an injured cord. The arrays have been designed with channels that allow nerve cells to grow across them and connect to other nerve cells. This technology has real potential as nerve cells can be guided to reconnect across the damaged cord, reforming connections and allowing for functional recovery. This is a new and exciting area of research and the addition of this capability to the SCIRF will provide novel pathways towards developing a cure for SCI. We have recently been given funding from an anonymous donor for a postdoc and PhD student; we will use these positions to develop this area of research. Within the next month we will be employing a medically trained bioengineer, who has expertise in this area. His role will be to develop the technology within the laboratory and develop new and exciting research projects in this area. For example, the postdoc will test the use of magnetic nanoparticles and electrical stimulation to encourage nerve cell regrowth.
3) Liposomes for drug delivery
A collaboration has been formed with Dr Zimei Wu (School of Pharmacy, University of Auckland) and Dr Justin Dean (Department of Physiology, University of Auckland) to test ways of packaging drugs for delivery directly to the site of a spinal cord injury. These packages (called liposomes) can be targeted directly to specific cells at the injury site, including both nerve cells and scar cells. This approach has an advantage over injecting drugs directly into the blood stream as it ensures that the drug will not be broken down in the blood stream and that the optimum dose can be delivered directly to the site of injury. This approach enhances the possibility of drug treatmmts being successful. A PhD student working on this project is currently generating the liposomes. Once these have been produced we will test them in our spinal cord model to determine if we can target specific cell types and over what time frame we can effectively treat the spinal cord after injury.
Please do not hesitate to contact me if you would like further information or clarification.
And finally, we would like to say thank you to the CatWalk Trust for their continued support of the SCIRF. CatWalk funding has been instrumental in helping us work towards our joint goal of finding a cure for spinal cord injury.
Simon O’Carroll
(on behalf of the Spinal Cord Injury Research Facility team)
