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MARC BUONICONTI: Thanks for joining me today. Can you please give me a little background, where you were born, where you grew up, where you went to school, at what point did neuroscience or science come into your mind?
DAMIEN PEARSE, PH.D.: I was born in a city called Brisbane on the east coast of Australia. When I was one, my parents moved to a mining town with a population of about 1600 people. I spent 16 years of my life living in the country, and during that time I grew a fascination with nature. I played with a lot of weird and wonderful creatures and from those experiences I eventually became interested in studying science. My parents actually were quite distraught initially when I chose to study science because they wanted to groom me as a lawyer, that was their 1st choice of what I was going to be and they told me almost every day that I was going to be a lawyer.
MB: Is your dad a lawyer?
DP: No. My dad worked in mining. When I got to the age of 16 I was rebellious and I didn’t want to follow what my parents had suggested me to do. I enrolled in college to be a bio-technologist, not a lawyer, going back to Brisbane, at Griffith University, to study. I spent 3 years there working on my Biotechnology degree, finding ways to design better beers, better paper processing and looking to work for industry. Although I enjoyed the field of work, I’d always had a strong interest in doing something that would be beneficial to society, to do something that would help people who are struggling in their lives. Thus, after I finished my biotechnology degree I jumped into the biomedical sciences, where I could impact human health, in the area of neuroscience for my Honors Research Thesis and then PhD. Because I basically had no background in neuroscience, it was initially a major struggle and I had to take lots of extra courses.
MB: Let me back you up a little bit. So you graduated undergrad in Brisbane and kept going onto your Ph.D. at the same school?
DP: Yes. In Australia the system is a little bit different. You normally pursue both undergraduate and graduate studies at the same college. During my undergraduate research rotations and classes I had met and worked with my future PhD mentor, Dr. John Leah. He was interested in understanding how gene expression was regulated within the central nervous system by the external environment. His work focused on determining the mechanisms that control the way genes are turned on or off in response to various sensory stimuli like vision and touch, and whether alterations in these controls occurred during aberrant sensations like pain. In my initial honors research work I focused on understanding how transcription factors, master switches that control gene expression, change between acute and chronic pain states, such as the difference between pain felt when touching something that is very hot versus an abnormal condition like persistent arthritic pain. Upon completion of my honors thesis I undertook my PhD research in which I examined how changes in gene regulation could contribute to the experience of pain and how one could perturb this signaling. During the final year of my PhD, I was fortunate enough to travel around the world, both for recreation and to undertake research internships abroad. While conducting research in Germany with Dr. Thomas Herdegen, I was introduced to the field of nervous system regeneration. Later in my travels, I attended the IBRO conference in Israel where Dr. Herdegen had suggested I attend a symposium of talks on regeneration. That is where I saw an outstanding talk given by Dr. Mary Bunge on promoting regeneration following spinal cord injury. Dr. Bunge had ended her presentation with an announcement that she was seeking a postdoctoral associate for her laboratory and so I met Dr. Bunge and was thrilled at an offer to go to Miami to interview for the position and to see the science being performed at The Miami Project. After coming to Miami and seeing The Miami Project, I felt it was a perfect fit for what I wanted to do. The field of nervous system regeneration was very hot, very exciting, and a holy grail of science. After I decided I would come to Miami, I undertook excellent post-doctoral training with Dr. Bunge for 3 years. During my research tenure with Dr. Bunge we demonstrated that by combining Schwann cell transplantation and the elevation of a signaling molecule called cyclic adenosine monophosphate we could substantially improve spinal cord injury repair and functional outcome. Wishing to continue this work and translate the approach towards clinical use, I stayed on at The Miami Project after my postdoctoral training and have currently reached the level of Associate Professor with my own lab.
MB: So, for those who may or may not know, you’ve taken Mary’s work and added your own twist to get us to that triple combination strategy that was talked about a few years back. How does it feel to come up with something - because I’m guessing you come up with a lot of things that don’t work out as planned - that did work, especially one that can potentially be a real pivotal point in an area of research, and how has it been received by the scientific community?
DP: Well, it’s difficult to understate how frustrating and difficult finding success in the field of spinal cord injury research is. If you’re lucky you might see some success in every 1 of 10 therapies that you test in the lab and often these effects are modest. It was therefore so exciting when we saw how effective the combination of elevating cyclic AMP and Schwann cell grafting was, it was just amazing. It was a very exciting time in the lab and at The Miami Project. I was taken aback by how fast everything was moving and that we could actually be looking at translating this bench top discovery to the clinic for people with spinal cord injury as a treatment. I felt the whole The Miami Project was invigorated. It was good to see the work of all our Miami Project researchers coming to the forefront and spurring more exciting discoveries. I was happy to see all the positive feedback from our supporters and the community, and that we could now actually be thinking about clinical trials. It was the enthusiasm that was generated during this time that helped us create the Clinical Trials Initiative and get us moving at top gear towards translating therapies to the clinic.
MB: In layman’s terms, how has it been received by the Neuroscience world?
DP: The work that we published is very highly cited, which means that other scientists have used our finding to generate further ideas and to move their research forward. So I would say that it’s been well received. Overall the scientific community is very enthusiastic that we’re moving Schwann cells as a therapy towards clinical trials and looking to do combination therapies in the future.
MB: So, as a scientist, you want to be able to jump as quickly as possible to the next level, the next stage, but unfortunately the way the system works you have to build a foundation first so this first trial is Schwann cell only and then we build on it with later trials. What do you think the results are going to be of the Schwann cell trial?
DP: So our initial Phase I trial is focused on safety and toxicity. We have a very small group of individuals with spinal cord injury that will receive Schwann cells and the clinical trial is not designed to show efficacy, only demonstrate that the transplantation procedure and therapy is safe. So, if the results demonstrate safety, then the trial will be a success. To show efficacy we need to undertake much larger clinical trials, termed Phase II and III, and enroll larger numbers of people with spinal cord injury; particularly because SCI has such a heterogeneity of injuries and functional outcomes.
MB: What’s the difference whether you do 100 or you do 10?
DP: Because you need to show statistically that the therapy is beneficial in comparison to a control group, such as the spontaneous level of recovery that is normally seen after SCI. It’s just the next step; the 1st step is to look at safety and toxicity. It doesn’t mean that we don’t expect to see a benefit of the Schwann cell therapy, only that with a low number of individuals in the safety trial and the design of the trial for safety, we may not be able to measure benefit statistically.
MB: In experimental models you have seen some amazing things with Schwann cells alone correct?
DP: Yes, we have seen that Schwann cells can improve function in a large range of experimental spinal cord injury models and particularly in both acute and chronic injuries. Looking at a Schwann cell graft after implantation into the injured spinal cord and the number of axons within the implant, it’s absolutely full of axons; I am hard-pressed to think of a single therapy that would be more supportive for axon growth, so I’m actually very excited about using Schwann cells clinically.
MB: So, you’re injecting the cells from within the injury and around?
DP: No, for now we are looking to inject Schwann cells just within the injured area of the spinal cord, to form a bridge across the injury site for nerve fibers to grow. Although the injury cyst is a hostile environment, transplanted Schwann cells can survive and support both axon growth and remyelination.
MB: I know in experimental models we tried to determine what type of sensation has or has not returned. That scares me more than anything; getting a motor response and being able to have some motion, but then being in such unbelievable pain. I know we tried to determine that based on pre-clinical experiments right?
DP: Yes, with animal models, we can assess whether therapies can induce or enhance pain, using paradigms of evoked pain – pain in response to a stimulus, like pressure on the skin. In these models we have seen that Schwann cells do not cause pain after transplantation into the injured spinal cord. However, a lot of the pain that is felt by people with SCI or other nervous disorders is spontaneous pain, where pain is felt, but it doesn’t appear to be caused by an external stimuli such as touch, it is not evoked. This type of pain is very difficult to not only understand but to model experimentally and is one of the reasons why developing medications to treat pain has been so difficult. That is why we must do a Phase 1 safety trial, to find out whether there are any potential problems associated with the therapy. Because we are looking at regenerative therapies, in which not only motor but also sensory axons could regenerate, we need to do these safety studies to find out whether we induce any pain.
MB: How many cells will we be injecting?
DP: The goal of the Phase I clinical trial is to use escalating doses of between 5 and 15 million Schwann cells. In our experimental models we’ve used doses of between 2 to 25 million. We will start off with low doses first to ensure the greatest safety in using the therapy. By injecting cells into the injury to fill the cyst and form a bridge across the injury site it would be good in the future to be able to tailor the dose of Schwann cells to the size of the lesion, as evaluated using imaging techniques such as MRI.
MB: If you put them in the cyst why wouldn’t you just put them all around through?
DP: Although many spinal cord injuries are functionally complete, rarely are injuries anatomically complete. That is, there is almost always preserved tissue around the injury that may contain demyelinated or silent axons, which if harnessed with a therapy could be important for restoring function. We hypothesize that Schwann cells may be able to remyelinate axons in this area and restore conduction. If we inject cells into these areas of preservation we may damage those axons or damage that tissue which could exacerbate the injury and reduce the effectiveness of the therapy or cause a loss of function. Therefore, we feel the safest method to go forward with first using a cell implant is to implant them into the injury cyst, as long as they can survive within this environment. In our experimental models we’ve shown that Schwann cells can survive when implanted into the injury cyst and mediate functionally relevant repair. We do however plan to look at performing perilesional injections in our larger animal models in the future to see if we can get a better result with this approach, but using this procedure will require extra care.
MB: Would the Schwann cells also be inclined to want to migrate within the spinal fluid?
DP: So the migration of Schwann cells is actually quite limited within the spinal cord. We see that the cells in our experimental models are confined largely to the injury cyst after injection. In some ways this is good because we don’t have to worry about Schwann cells potentially migrating all up and down the central nervous system (CNS), although Schwann cells are normally found in many regions of the CNS and throughout the peripheral nervous system (PNS). In my lab we are looking at ways to enhance the migration of Schwann cells, at least initially after injection into the spinal cord, because if Schwann cells are not able to migrate out of the injury they may not be able to reach retracted axons and guide them into, as well as out of the lesion or reach demyelinated axons that may be far from the injury. We have been looking at ways to modify the Schwann cell surface so that they can ignore signals that restrict their migration to the lesion. We are working with our collaborators; Dr. Rutishauser and El-Maarouf, at The Sloan-Kettering Institute, on a molecule called polysialic acid which prevents cells from interacting with each other. We have seen that when Schwann cells have polysialic acid on their surface that they migrate out of the injury site and are much better at supporting axon regeneration and restoring function after SCI. So as you said before, Schwann cells are just a building block or a foundation therapy that we hope to build upon with combinatory approaches to dramatically enhance their ability to repair the injured spinal cord.
MB: Are you doing some trials with that now?
DP: So we are working with our collaborators on pre-clinical models to improve the translation of this combination approach to clinical use and find a way to only modify the Schwann cells for a short-time to avoid them from migrating too far from the lesion. Again, it’s a matter of just getting that 1st building block, with the Schwann cell therapy, to clinical trials. From there I think there’s so many exciting combinatory approaches that we can look to move forward with Schwann cells.
MB: So it’s there, it’s with the FDA. Where are we right now? (December 2011)
DP: At the moment the FDA are looking for additional evidence that the Schwann cells don’t extensively migrate and potentially cause damage or toxicity in other regions of the CNS, in the experimental studies that we’ve already completed. So we’re currently doing additional histology work, looking at other regions of the CNS to provide this evidence. We have not observed migration of the cells outside of the immediate lesion site in previous work so we don’t expect to see any problems, so it’s just some confirmatory work that needs to be carefully done.
MB: Is that it?
DP: That’s largely the work that we have to do, as well as supply additional information regarding how our studies were conducted.
MB: So what is the timeframe for that process? Do you think we’re pretty close?
DP: We have the histology core lab cutting and staining like crazy and the preclinical teams are working around the clock.
DP: I think we’re within months of being able to answer those questions. It’s not something that can be done in a week. We’ve done a lot of histological processing of our tissue samples but we’ve concentrated on just the injury site, this additional work pretty much extends to the entire brain and spinal cord, so it’s quite a lot of cutting, sectioning, staining, and analysis. It’s time consuming and laborious, but the good thing is we’re not expecting to see anything out of the ordinary.
MB: Anything else you want to say I mean, how does it feel to be on the tip of the spear as they say?
DP: I think that The Miami Project is making tremendous strides. I would never have envisioned as a postdoc that we would be moving to clinical trials so quickly and everything has happened so fast in the last 5 years. The Miami Project has outstanding basic research, pre-clinical therapy development and clinical work; now we are looking to translate therapies we have developed here to clinical trials. As scientists, until you do it, you don’t completely know how to take a therapy from the bench forward to the clinic. We have had lots of cutting edge discoveries and I think making exciting discoveries and having an excellent supportive team and community has inspired us all to basically take it up another notch in our work to move these discoveries to the clinic. We’ve also brought on board additional expertise from outside and that has made a big difference in moving this first clinical trial into reality. We’ve learned so much that it shouldn’t be a problem moving forward with additional trials after this one is under our belts. I’m expecting many more clinical studies with therapies developed by Miami Project researchers to go forward in the future.
MB: Let’s talk about one last thing. The chronic model, this trial is a sub acute, by the time they get all said and done it’s 3 weeks or a month after the injury for this trial?
DP: It will be 3-5 weeks after SCI that Schwann cells will be used clinically.
MB: Do you have any reason to believe this can’t also be done in a chronic SCI model?
DP: In our experimental models we saw that we could obtain a similar beneficial effect both on axon regeneration as well as functional outcome in chronic SCI, so that was very exciting to see.
MB: That will be step 2 right, as soon as we get the green light for this initial trial we can submit the next one for chronic injuries?
DP: One of the things about chronic injuries is that you can establish a very good baseline before the therapy is used, and basically the person can be their own control. So when we introduce Schwann cells we’ll be able to have very good resolution at picking up any beneficial effects with someone who has a stabilized chronic injury.
MB: So would you anticipate, assuming everything goes well for the first research participants, maybe modifying the initial IND to include chronic injuries, or is that a complete new study?
DP: For sure we’ll have to do some extra experimental work, but it will be much less than what we have done previously for the acute SCI IND, and we have a lot of experience now in submitting an IND so basically we would be looking at submitting an amendment to the original IND. By comparison that would actually be a small amount of work as far as the paperwork and some additional studies that would be needed, but hopefully we can follow very quickly with that submission.
MB You kind of referenced it earlier, but in terms of the Schwann cells being a huge building block that we build off of, being a scientist and knowing some of the things you already know in The Miami Project pipeline, what kind of things do you see being the most promising to add to Schwann cells?
DP: I think polysialic acid, cyclic AMP elevation, addition of growth factors and some work from Dr. Bunge’s lab is showing that addition of neurotrophins can dramatically enhance the remyelination effect of Schwann cells. With polysialic acid, you can get migration of cells in significantly large numbers of axons of the brain to grow across Schwann cell grafts. There is also rehabilitation and conditioning that may be able to enhance the effectiveness of Schwann cell implants. So I think there are more than enough additional complimentary therapies that we can look to add to Schwann cells from the other exciting programs of Miami Project researchers.
MB: We’re doing all of these right now?
DP: We’re gathering as much experimental evidence of how these therapies work in animal models so that once this initial Schwann cell Phase 1 clinical trial goes through, we’re ready to continue.
MB: Well I would think that you would do your triple combination therapy with polysialic acid together, no?
DP: So in an ideal world it would be great to have a multi-faceted combination therapy to address all the problems of spinal cord injury because it is a very complex condition. With such a complex condition, it’s likely a complex therapy will be needed. You have to think, however, of possible toxicities or safety concerns that may be created when these agents are combined, so you need to provide a lot more information with your IND submissions and they’re evaluated with even more scrutiny the more you add. So you have to think of all the interactions.
MB: So we may be looking at a time in the coming years where we may see Schwann cells, and other compounds working in tandem with mild hyperthermia for the acute and chronic SCI.
DP: Sure, targeting different phases of the injury or targeting different facets of the injury is important from a combinatory approach and we have some of the leaders in neuroprotection research at The Miami Project. Safe to say, this is the most exciting time that you can think of in SCI research. When I came to Miami, I would never have imagined I would see some of the most complex therapies moving forward or envision that therapies could promote extensive axon regeneration after injury. Everything happening at this time is just amazing. It’s great to be a part of it.