An overview of the projects that have been granted funding in the 2018 year:
The use of gene therapy in combination with enriched cell transplantation in a chronic model of SCI.
|Host institution||The University of Auckland|
|Research location||Centre for Brain Research|
|Lead investigators||Dr Simon O’Carroll and Mr Connor Clemett|
|Funding term||20 February 2019 – 30 November 2021|
Repair of the damaged cord with stem cell implants is an exciting therapeutic development but its potential is currently limited by the formation of scar tissue within the injury. The Spinal Cord Injury Research Facility (SCIRF) lab, here in Auckland, New Zealand, has recently developed a method to express a “scar busting” enzyme within the injured cord which along with exercise rehabilitation leads to improved outcomes. The aim is to combine the gene therapy approach with the addition of stem cells to promote recovery.
PhD student, Connor Clemett, has started a project to combine this approach with cell therapy. Connor will inject cells into the injured cord that wrap around the nerve cells and improve the connection with other cells. This approach aims to make the new connections that occur stronger, leading to even better outcomes. In future we hope to use a new technology where we can grow these cells from an injured persons skin cells and, by using their own cells, increase the chance that such an approach will be successful
SPINAL CORD INJURY RESEARCH FACILITY (SCIRF)
|Host institution||The University of Auckland|
|Research location||Spinal Cord Injury Research Facility (SCIRF)|
|Director||Dr Simon O’Carroll|
|Technical Manager||Barbara Fackelmeier|
|Funding term||1 August 2018 – 31 July 2020|
This funding covers costs of a Technical Manager to manage the day-to-day running of the Facility and provide expert technical support and training for animal care, processing and data analysis; the use of high-containment amenities in which the technical team carry out experiments in a controlled environment; and a Student induction programme to introduce undergraduate biomedical science and medical students to the fields of SCI research.
A number of existing and new projects continue to grow and progress in the lab and under the leadership of Dr Simon O’Carroll, the team of specialist researchers is increasing, which in turn attracts additional funding from other sources.
- Blocking chronic inflammation – to test an existing drug (Tonabersat) to stop chronic inflammation, being carried out by Sheryl Tan and Barbara Fackelmeier (and an MSc student Miran Mrkela), is almost complete with results expected in the coming weeks.
- Use of multielectrode arrays for guidance of nerve cells – this work, being carried out by Dr Sam Paritt and Dr Zaid Aqarwe (a holder of the prestigious Neurological Foundation O’Brien Clinical Fellowship), and a PhD student Anusha Dravid, uses electrical signals to promote nerve cell growth in the cord. They have developed ways of testing the effect of electrical signals on nerve cells taken from the spinal cord and are able to place out electrodes onto the spinal cord and take readings before and after injury. They will now study the changes in signals that occur with the goal of stimulating the spinal cord to return the signals to normal.
- Targeted drug delivery – A project, carried out by an MSc student Julia Newland, to test the use of small packages (called liposomes) for targeting drugs directly to the site of a SCI has now been completed. This approach means drugs will not be broken down in the blood stream and smaller doses can be used, meaning that unwanted side-effects are less likely. The project found that they are able to target these liposomes to the cord. The next step is to further develop these to improve targeting to the cord; and then test drugs known to protect the spinal cord after injury to see if targeted delivery gives better results or means giving lower doses.
Balance is everything – optimising the cell combination for three-dimensional nerve bridges
|Host institution||Griffith University|
|Research locations||Gold Coast and Brisbane, Australia|
|Lead investigator||Dr James St John|
|Funding term||June 2018 – June 2019|
Methods to repair the injured spinal cord have received a boost by new advances in how cells are grown in the laboratory. It is now possible to rapidly grow a “nerve-in-a-dish” that replicates the supporting structure of nerves within the body. This means that nerve bridges with pre-formed stable connections can be transplanted into the injury site resulting in better survival and integration, and leading to improved functional outcomes. This project will optimise the balance of different cell types within the nerve bridges to maximise their therapeutic benefit for repairing the injured spinal cord and reversing paralysis.
The use of gene therapy in combination with Hindlimb-specific rehabilitation in a chronic model of SCI.
|Host institution||The University of Auckland|
|Research locations||Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences|
|Lead investigators||Dr Simon O’Carroll and Dr Jarred Griffin|
|Funding term||1 September 2018 – 31 March 2019|
Following on from his PhD work that used gene therapy to break down scar tissue along with exercise rehabilitation, Dr Jarred Griffin started a project using this approach for chronic SCI (long-term wheelchair users). This project applies the therapy to a chronic injury model to give an indication if the genetic therapy to break apart scar tissue used in combination with rehabilitation, can reverse damage much later after the initial injury.
The Spinal Cord Injury Research Facility Progress Update Dec 2018
It has been another exciting year in the Spinal Cord Injury Research Facility (SCIRF) as the team works on a number of projects developing treatments for spinal cord injury. This is due to the support from the Catwalk Trust in establishing the Facility, which has allowed us to develop a team of researchers and attract funding from other sources to develop and grow our research.
Blocking chronic inflammation
The project to test an existing drug (Tonabersat) to stop chronic inflammation, being carried out by Sheryl Tan and Barbara Fackelmeier and an MSc student Miran Mrkela, is almost complete and we will have results by the end of the year.
A number of projects are underway to test gene therapy approaches to treat spinal cord injury. Following on from his PhD work that used gene therapy to break down scar tissue along with exercise rehabilitation, Jarred has now started a project using this approach after chronic spinal cord injury. If this shows the same benefit as his previous study, this has real potential for people currently in wheelchairs, as well as those with new injuries. A PhD student, Connor Clemett, has started a project to combine this approach with cell therapy. Connor will inject cells into the injured cord that wrap around the nerve cells and improve their connection with other cells. This approach aims to make the new connections that occur stronger, leading to even better outcomes. In future we hope to use a new technology where we can grow these cells from an injured persons skin cells and by using their own cells increase the chance that such an approach will be successful.
Use of multielectrode arrays for guidance of nerve cells
This work, being carried out by Dr Sam Paritt and Dr Zaid Aqarwe (a holder of the prestigious Neurological Foundation O’Brien Clinical Fellowship) and a PhD student Anusha Dravid, to use electrical signals to promote nerve cell growth in the cord is progressing well. We have developed ways of testing the effect of electrical signals on nerve cells taken from the spinal cord and we are able to place out electrodes onto the spinal cord and take readings before and after injury. We will now study the changes in signals that occur with the goal of stimulating the spinal cord to return the signals to normal.
Targeted drug delivery
A project, carried out by an MSc student Julia Newland, to test the use of small packages (called liposomes) to targeting drugs directly to the site of a spinal cord injury has been completed. This approach means the drug will not be broken down in the blood stream and smaller doses can be used, which will mean that unwanted side-effects are less likely. We found that we are able to target these liposomes to the cord. The next step is to further develop these to improve targeting to the cord and then test drugs known to protect the spinal cord after injury to see if targeted delivery gives better results or means we can use lower doses.
(on behalf of the Spinal Cord Injury Research Facility team)
26th June 2018
CatWalk funding expedites clinical trials into SCI research at Griffith University
CatWalk Spinal Injury Trust (CatWalk Trust) continues to pursue its mission of a world free of paralysis caused by spinal cord injury, announcing a NZD $75,000 grant towards research being undertaken by the Clem Jones Centre for Neurobiology and Stem Cell Research at Griffith University in Brisbane, Australia.
The core project, which is funded by the Queensland State Government and the Perry Cross Spinal Research Foundation, is investigating how cellular intervention can promote repair and regeneration within the spinal cord following an injury, in particular the capacity to grow nerve bridges that can create stable connections within the injury site.
The researchers achieve this by growing a combined culture of two types of cell – “fibroblasts”, a type of cell that provides structural and biochemical support to the surrounding cells, alongside “olfactory ensheathing cells” (OECs), a type of cell found in the nervous system that helps to provide nutrition and physical support – which are then introduced to the area surrounding the damaged spinal cord.
The co-culture, called a nerve bridge, is then introduced to the hostile environment around the damaged spinal cord, where it helps to foster interactions to stabilise the environment, and allow the damaged spinal cord to begin a process of repair or regeneration.
The research has already shown promising results in the creation of two-dimensional cells grown in within the lab, and the researchers have also successfully constructed three-dimensional cell constructs. The next step is to determine whether the nerve bridges they produce are healthy, and whether they will continue to be healthy once they are introduced to the damaged spinal cord.
“We now know we’re able to produce the cells, and we have conducted successful tests in two-dimensional models,” says Associate Professor James St John, who is leading the research project.
“But the real-world application will happen in three dimensions, and that is where our focus is currently. The bigger the cell nerve bridges get, the more complicated the process becomes, and the more variables there are to practical application in a clinical environment.”
Chief among those variables, says Assoc Prof St John, is the ratio of fibroblasts to OECs, and the density of the three-dimensional culture. But it’s not a simple process, and one that relies on a lengthy process of trial and error, working closely with clinicians to address the technical requirements of the treatment.
It’s a process that Assoc Prof St John likens to building a bridge over a river, in that the cellular nerve bridge must meet every possible variable in order to function properly.
The funding from the CatWalk Trust will be directed at addressing those variables, to accelerate the clinical trials process utilising three-dimensional nerve bridges. It means Assoc Prof St John and his team will be able to conduct higher risk trials, which could produce better results in clinical therapy.
“We are now trying to get to a stage where we can demonstrate positive outcomes in clinical trials, and the CatWalk Trust grant is critical in helping us to expedite the process of checking the many, many variables that arise in a real-world environment,” says Assoc Prof St John.
Catriona Williams MNZM, founder of the CatWalk Trust and a C6/C7 tetraplegic, says that directing funding towards speeding up the clinical process is typical of CatWalk Trust’s dedication to supporting pioneering and ground-breaking research projects, and its tireless efforts to get people out of wheelchairs and back on their feet.
“New Zealand has one of highest rates of spinal cord injury per capita in the Western world,” she says. “Every year, between 80 to 130 people per year suffer an acute spinal cord injury – one that results in paralysis.”
“Spinal cord injury has an overwhelming impact here in New Zealand, as it does in Australia, and the opportunity to speed up new therapeutic interventions like those being investigated by Assoc Prof St John and his team was a major driver in CatWalk Trust awarding the funding grant.”
Assoc Prof St John agrees, saying that speeding up the clinical process is where the research will have its most demonstrable impact.
“We are essentially trying to do everything at once – the real driver being to get our research out there as fast as possible,” he says.
For Catriona Williams, and for others living with paralysis caused by spinal cord injury, it can’t come soon enough.
Research Update – May 2018
Axons are the long thread-like part of neurons along which electrical signals are conducted along to other cells. Growth cones are fascinating extensions of an axon, which seek its distant synaptic target – they are like a hand with wiggling fingers that sense the surrounding environment. Guided by these tiny hand-like structures, axons in the human body can be up to 50 cm long, stretching from the brain down the spinal cord to find its correct target connection. This is the equivalent of a person in Auckland growing their hand all the way to Dunedin and finding a specific person guided only by their perfume.
You can also imagine how disruptive it would be to break these long communication pathways in the form of a spinal cord injury. Here at the Spinal Cord Injury Research Facility, within the Centre for Brain Research, we are creating new ways to stimulate growth cone regeneration to form new functional connections after injury.
Jarred Griffin, BSc (Hons), PhD Candidate, Spinal Cord Injury Research Facility, Auckland University
Catwalk Progress Update November 2017
The Spinal Cord Injury Research Facility continues to make significant progress in a number of research areas to develop cures for spinal cord injury. We have a busy summer ahead with 6 summer students joining us to work on new or ongoing projects.
Blocking chronic inflammation
Based on our work showing the protective effects of using our connexin channel blocking peptide to prevent inflammation early after injury , we now believe that using a similar approach to block ongoing inflammation will reduce neuropathic pain and create an environment that allows repair to occur. With funding from the Catwalk Trust, a project is underway to test an existing drug (Tonabersat) that we have identified as a channel blocker. This drug has the advantage that is has been used in several phase two clinical trials, including long term prophylactic use for migraine prevention and is proposed as a treatment for epilepsy. We have developed an improved dosing profile and already have data for central nervous system (CNS) treatments.
This project, carried out by PhD student Jarred Griffin has been eevaluating theuse of gene therapy to deliver a protein that breaks down scar tissue after injury and allows regrowth and reconnection of nerve cells and has shown some really exciting results. We know that this treatment reduces the size of the injury, reduces the amount of scarring and allows nerve cells to regrow and reconnect. We have also carried out experiments where we have used the gene therapy in conjuction with exercise rehabilitation. This rehabilitation strengthens the nerve connections to the limbs and in our experiments we have seen an even greater improvement in walking and coordination. These experiments show that combining different approaches will be the way to finding a cure and our future plans are to combine a number of the approaches we have been developing to provide the greatest benefit possible.
Protecting blood vessels
Following spinal cord injury, blood vessels are damaged and this leads to the injury becoming worse. Work by three students in the lab, Connor Clemett, Laverne Robilliard and Andrea Gu has made some important advances in understanding how blood vessels are affected by injury and how we can protect them. Andrea and Laverne’s project’s have discovered some interesting findings about how the blood vessels change with injury, which will help us design ways to regrow them after injury. Connor’s project tested compounds to strengthen the blood vessels and has made some really exciting findings about how we can protect blood vessels against the damage that occurs.
A number of new projects are also progressing well
1) Use of multielectrode arrays for guidance of nerve cells
A collaboration has been established with the School of Pharmacy, University of Auckland and the Freiburg Institute for Advanced Studies, Germany to test the use of multielectrode arrays to measure electrical changes that occur with injury and use electric currents to guide the growth of nerve cells across an injured cord. We have designed and tested a microelectrode array and can measure electrical signals in the cord. This is an important first step in being able to stimulate the cord after injury to regrow nerve cells. This technology has real potential as nerve cells could be guided to reconnect across the damaged cord, reforming connections and allowing for functional recovery.
2)Targeted drug delivery
A project is underway in collaboration with researchers from the School of Pharmacy and Department of Physiology at the University of Auckland to test ways of targeting drugs directly to the site of a spinal cord injury. This is done using small packages (called liposomes) that can be targeted directly to specific cells at the injury site, including nerve cells and scar cells. This approach has an advantage over injecting drugs directly into the blood as it means that the drug will not be broken down in the blood stream and the optimum dose can be delivered directly to the injury. It also means that the amount of drug that is needed can be reduced, which will mean that unwanted side-effects are less likely. Side effects are a major issue with some drugs being currently tested and this approach could allow smaller doses to be used, avoiding this problem. A student, Julia Newland, is testing the best time to deliver these liposomes to the injured cord. Over the summer we will test targeting drugs to scar forming cells with the next step being to test these drugs in our model of spinal cord injury.
(on behalf of the Spinal Cord Injury Research Facility team)
Neurons within the spinal cord – October 2017
PhD student Jarred Griffin explains has sent this image of neurons within the spinal cord. ;“Within the human spinal cord there are an astonishing 1 billion of these neurons. Like power lines, neurons conduct electrical signal from the brain to the body that convey important information regarding to movement and sensation. Within the Spinal Cord Injury Research Faciltiy at Auckland University we have created a genetic therapy that stimulates damaged neurons to regenerate after injury therefore restoring lost functions.”
Injury Size – September 2017
Spinal cord injuries result in loss of the tissue that is important for connections from the brain to the body. PhD student Jarred Griffin explains; “At the Spinal Cord Injury Research Facility we have several lines of research that are showing promise to prevent the initial damage or to regenerate and replace the missing tissue leading to improved motor and sensory recovery. These avenues include the connexin peptide neuroprotective therapy, the scar-busting gene therapies, exercise rehabilitation, blood vessel protection, and regeneration-promoting electrical stimulation”.
Following spinal cord injury blood vessels in the cord are damaged and become leaky. This allows blood to get into the cord and this worsen the damaged and makes the size of the injury larger. The animation shows a leaky blood vessel within the spinal cord in green and invading inflammatory blood cells shown in red. Three Honours students: Connor Clemet, Laverne Robilliard and Andrea Gu are currently underway in the lab to understand changes that occur to blood vessels after injury and test drugs that will help protect or repair the damage.
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.
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.
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.
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.
(on behalf of the Spinal Cord Injury Research Facility team)