Recently we have had news of some major research developments from Ohio, so we asked two of our funded researchers in the city to tell us more about their work and collaborations.
Dr Pippa Warren is carrying out a study of breathing recovery in high-level and chronic spinal cord injuries in Dr Warren Alilain’s laboratory at the MetroHealth Medical Center, Case Western Reserve University. In November she reported that breathing function could be fully restored in animals with high-level injury using the enzyme chondroitinase, which breaks down the scar tissue around the injury, combined with exposure to intermittent periods of low oxygen.
Pippa’s study gives laboratory rats with spinal cord injury a mixture of air with a lower concentration of oxygen for short periods of time on most days. This doesn’t involve any effort for the rats and they usually just go to sleep. While they are sleeping the low oxygen level causes them to breathe more deeply, and it is this deep breathing combined with the breakdown of the injury scar by chondroitinase that appears to enable nerves to reconnect, strengthen any spared connections and allow natural breathing to be restored.
The combination of the two treatments boosts serotonin levels around the injury site and stimulates the nerve cells. Serotonin, a neurotransmitter, is naturally produced by the body and is widely known for its role in maintaining mood and reducing anxiety and depression. In this study it has helped to reconnect nerves and reverse the paralysis of the diaphragm.
Not only was the combined treatment successful in most cases but it even worked for animals with long-term injuries. Her study included some rats with injuries up to 18 months old, close to the animal’s natural lifespan.
Pippa said “One rat had had diaphragm paralysis for 18 months – it had been injured for 70% of its life. This is equivalent to being injured when it was a teenager, and receiving a treatment when it was about 70 years old. I gave it a treatment and, amazingly, it worked.”
“We were thrilled by the results. Chondroitinase on its own had very modest effects on diaphragm function immediately after trauma, but we hypothesized that it would work better in chronic injuries. In acute cases, shortly after injury, the scar is still being made, but in chronic injuries the scar is complete. If we can break down the scar with chondroitinase at this stage it won’t be renewed. This is incredibly positive news for people with long-standing injuries.”
Pippa’s research was successful in recovering breathing function in two-thirds of the animals in her study. These results are incredibly encouraging for people affected by high-level injuries.
The remaining questions of safe delivery of chondroitinase to the injury site and its containment and control once in situ are the subject of another major study Spinal Research is funding with a consortium of researchers in London, Cambridge and the Netherlands.
Pippa says “Our work has increasing clinical relevance – we are dealing with cervical injuries which are the most severe and common, and chronic injuries. We are now moving on to look at a contusion injury model for this breathing project. We are moving into these more clinically relevant models and we’re trying to see how the treatment affects multiple systems. You apply one treatment and it could have different effects on different functions. We want to optimize our treatment program so that moving forward with this strategy we get a very specific and appropriate dose to make the treatment the most effective. Luckily the respiratory motor system for the rat is very similar to other species, which means we can reasonably assume that you’d get similar results across species”
“Respiratory and motor problems are fundamental and we want to improve people’s quality of life. Getting people to breathe normally would be great but getting people off ventilators would be a huge improvement in quality of life. We can also aim to reduce respiratory-related disorders which can be life-threatening.”
“We are grateful for the funding that has enabled us to do this study. It shows that we shouldn’t write off an injury because it’s an old injury – functional recovery is still possible.”
Spinal Research is delighted by the progress Pippa is making in the Alilain laboratory. After receiving a Nathalie Rose Barr studentship award for her Cambridge PhD, Pippa wanted to continue her research into spinal injury repair and, while presenting her doctoral work at our annual Research Network Meeting, got talking to Dr Alilain. “It really is a fantastic meeting, not only for students but also other researchers. You can forge collaborations with other labs and help the field progress.”
She decided to move to Ohio where her post-doctoral research is being supervised by Dr Alilain and Prof Jerry Silver. “Both are highly involved and incredible mentors for me and for the project. The Alilain and Silver labs are separate facilities in two different locations but we have close collaboration. Peter MacFarlane’s lab in Ohio has also collaborated with us – we would like to thank them for their support. It’s a really great atmosphere and a great team of people we have here in Cleveland.”
Professor Jerry Silver commented on the study “Serotonin is very important in allowing the remaining fibers to work much better. The treatment just involves one series of injections into the spinal cord, that’s all that’s needed. The spinal cord is rewiring itself. The questions now are about how much of the treatment to give, when to give it, and when to stop.”
Prof Silver and his team are working on a range of combination strategies, which offer the best hope of future treatments for patients. Different combination therapies are likely to be valuable in recovering different functions.