I'm going to introduce Dr. Alan Levy, who is the chair of the Department of Neurological Surgery at the University of Miami Miller School of Medicine. Dr. Levy holds appointments in neurological surgery, orthopedic, and early habitation medicine. He's received his medical degree at the University of Ottawa and completed his neurosurgery residency training in Toronto. Dr. Levy follows the footsteps of his mentors, Dr. Sontag, Dr. Charles Tatar. He is married to Teresa Rodriguez, an internationally known, award-winning news anchor for Univision, which I have not known until I did my research. So he has four children, although I met her at the reception, and I should have recognized that. He has four children. A little tidbit about him, he is fluid in French and Italian. We know Dr. Alan Levy is an outstanding teacher, leader, pioneer, and researcher in neurosurgery. So please help me to welcome Dr. Alan Levy. Thank you very much for that introduction, and it's an honor to be here and update you on the Miami Project. And the Miami Project has been around now for 32, almost 33 years. So I thought, these are my disclosures, I thought it would be important to sort of give you a historical perspective, especially probably since some of the younger people in this room weren't even born when the Miami Project started. And so, I would just take a second, play this videotape, so narrated by none other than Howard Cosell. Howard Cosell, the father, the son, Mark Bonacani, injured, playing middle linebacker for the Citadel against East Tennessee State, and terribly injured, apparently. And my heart goes out to them, because all you can do now is pray. Pray for young Bonacani. So those words, you know, pray for young Mark, and I'm sure a lot of praying was done after his injury. He ended up eventually in Miami under the great care of Dr. Barth. Green had a C2 injury, so high quadriplegia, and back in those days, 32 years ago, it wasn't uncommon to spend six to nine months in the hospital, including between the hospital and rehabilitation. Things are much, much different now. But, you know, Nick, a very impressive guy, played football, an attorney, a very successful businessman and broadcaster, wasn't only going to pray and wanted to do something. And so he approached Barth in those days and said, you know, we need to fix this problem. And that's how the spark that sort of started the Miami Project. And at first, it was just really a couple of labs, and really not a defined name at that point. I've worked in the Miami Project for 25 years in some fashion. And what always, you know, what I didn't quite understand when I started was this name. It's a pretty bold name, the Miami Project to Cure Paralysis. And I think it's also important to sort of get a background of, you know, how that started. So I'm sure most of you in the room know what the Manhattan Project was. And the Manhattan Project was a conglomeration of scientists from different countries, engineers, technicians, and they all came together in between 1942 and 45 to develop the atomic bomb during the Second World War. So that Miami Manhattan Project turned into the Miami Project. And then when you think of, like, well, what's it for? Obviously it's to try to reverse paralysis or treat or remedy. Cure obviously is the most strong word that you could ever use. But that's how it started, Miami Project to Cure Paralysis. And again, it has a huge history now. Started in the bowels of the medical school. Lois Pope donated money to create a building which houses neurosurgery in the Miami Project. We talked about Barth Green and how integral he was in starting it. And then we've had three scientific directors. Richard Bungie unfortunately passed way too early. He was my scientific mentor way back. And then Dalton Dietrich has been the scientific director now for about 18 years and has done an amazing job carrying the torch. There are over 25 full-time scientists. We have six neurosurgeons who work in the Miami Project. And this is the faculty. And it's certainly the research arm that fuels our department in terms of research. So we're ranked number four in NIH funding. 85% to 90% of that is NIH funding through the Miami Project and maybe 10% through other efforts including the Brain Tumor Institute and the Vascular Institute. And while early on a lot of the support was philanthropic, now these days most of the support is actually grants and much, much less philanthropic support. We're located in Miami, not a bad place to live and work, not too far from the ocean. And one of the missing elements in this whole picture has been our pretty old rehab center. It's about 45, 50 years old. I always find it painful sending our patients there. Not that the people aren't good, but the bricks and mortar are horrible. And in 2019, there'll be a brand new building, which is a collaborative effort between Jackson Memorial and the medical school, which will house our new rehabilitation center, for which we are very excited. So those few minutes just to describe what the Miami Project is. And now I was going to talk a little bit about the research, which is extremely broad. And I'm not going to be able to touch on everything. Everyone in this room pretty well knows the incidence of spinal cord injury, the main causes, and how many people are affected. But I think rather than just trying to figure out one drug or one cell, what the Miami Project tries to do is sort of look at it from a holistic approach. So not only neuroprotection and regeneration, but rehabilitation, quality of life, fertility, education and training, and certainly education and training of many of the students, if you will, who have come through there. And that we're not just a spinal cord injury research institute. There's lots of work being done in traumatic brain injury, stroke, and neurodegenerative disease. Probably not to as great an extent, but there's certainly a huge synergy between spinal cord injury and brain injury. And if you can figure out how to cure one, you might be able to help the other. The other thing I think is very important to know is that you find something in the lab, you translate it into the clinic, and undoubtedly you'll learn things from the clinic that you'll have to bring back into the lab and fix. And I think that's a very important part of translational research. I think people think it's just one arrow straight and a fix. And certainly we've seen that in our clinical trials. I'm just going to talk about a few exciting areas in the basic science area and then move on to some of the clinical trial work. But of the 25 labs, this is an example of a lab that's involved in high-content screening. So basically looking at molecules, enzymes that they see in a culture dish that promote regeneration. And so identifying drugs through this method and then eventually testing it in animals to see how it affects neural regeneration. And this is an example of a potent kinase that was identified that truly resulted in remarkable axonal growth. And again, working with industry to hopefully commercialize it. Another area that's very exciting, and this is mostly stuff that comes from Jay Lee's lab. I'm here showing you retinal axon regeneration, but there's obviously very close parallels to optic nerve injury and spinal cord injury. And one of the exciting things that he's doing is that we really need to be better at quantitating regeneration. I think in the old days, we would just do tissue sections and count the number of axons. And that's not the best way to look at things. And so now with the new imaging strategies, confocal microscopy, but optogenetic imaging, you can actually get a 3D image of what an axon is doing. And sometimes you see a lot of staining, but the axon's absolutely going nowhere. So trying to figure out whether you're getting true regenerative effort is important and can be done, both in the optic nerve and in the spinal cord. So I was going to focus on two areas, neuroprotection and cell transplantation. You'll hear a lot in this meanings of methylprednisolone and different neuroprotective strategies. Many are listed here. Many have been in trials. Many will be in trials. And many have, unfortunately, failed trials. We've been working on cooling now for 12 years, lots of basic science evidence, not only from us, but many other labs, including Toronto, suggesting that cooling the spinal cord can be effective in improving behavioral outcomes and reducing tissue injury. This is a nice paper from Damien Pierce looking in the cervical spinal cord in the rat and doing a lot of quantitation of neuronal preservation. There's also, while traumatic brain injury has a pretty muddy course with cooling, there is other diseases out there like post-traumatic, not post-traumatic, but post-cardiac arrest brain injury. When people have arrests, cooling is part of the hypothermia or hypothermia is part of the protocol of resuscitation because it improves neurological outcomes after those types of injuries. So we've been doing intravascular cooling with cooling catheters. And we find that that's the most accurate way of keeping the body cooled. And this is showing some of the early patients that we treated, showing that intravascular cooling equals CSF cooling, and that's what we've stuck with over the time. There are other ways to cool. And we started a trial now 12 years ago looking at cervical patients, Asia A, with these age categories had to be blunt injury. These initially were the exclusion criteria. We wanted to look at the most severe injury. We did a protocol, which is what you would expect, including a Doppler ultrasound when the catheter was removed. And this is what a typical temperature profile would look of a patient, two to three hours of rapid cooling, hypothermia for 48 hours, and then slow rewarming and trying not to get any fever during the hospitalization. And we published our first 14 patients now about seven years ago. Then we published our next 35 or 38 patients back in 2013. And the essential findings were that about 40% converted from one Asia grade, usually Asia A, to another, that the complication profile was similar to non-hypothermia treated patients. So we had a historical cohort to look at that using a cooling catheter didn't exponentially or increase DVTs or PEs. And so this was the spine and peripheral nerve section recommendations on cooling, that it was safe, and that we have to do further studies to see where we're at in terms of natural history comparisons. We started a multi-center DOD study about a year or so ago involving Grady, Jefferson, and Methodist. Ben Rogers is the PI at Methodist, and Dr. Ahmad, and Dr. Harrop. And that is ongoing and includes a non-injured or an injured non-cooled group. And so hopefully we'll have word for you about how that is going. So cooling and neuroprotection is one strategy. But ultimately, for some of the more severe injuries, you have to look at cell replacement. No neuroprotective strategy is going to cure someone's spinal cord injury when there's tons of central tissue injury in the more severe injuries. So fixing that, replacing cells, restoring connections are critical. There's been a lot of hope in the newspapers and TV on stem cells. I think most people in this room understand that not every stem cell is the same. I'm sure the lay public thinks that all the stem cells are the same and they're all fantastic. But there's major differences between a mesenchymal adult stem cell and an embryonic stem cell or a fetal stem cell in their ability to transform into other cells. I mean, the simple is adult mesenchymal stem cells don't transform into neurons or oligos. They can secrete good things that could help. But you really need more immature type cells to actually change into neurons or oligos and repopulate the nervous system, which is what we want after a serious spinal cord injury. And you've got to have a good handle of what the stem cells do. There's lots of tragic stories of people going internationally, getting stem cell injections, and then coming back and developing tumors of the nervous system. So whatever stem cell you use, you need to characterize them well and not put your patients at risk. So there were three stem cell trials that were going on. None are actively recruiting any patients currently. I'm going to talk to you a little bit about the Stem Cells, Inc. trial that we were involved with and were the biggest recruiting site. These are the inclusion criteria here. So these are stem cells for chronic injury. And chronic injury is defined as anyone after four months of injury. And they have to be less than two years since the injury. And there was a dose escalation part. There was a random assignment part. But one of the, and I was mentioning this this morning, one of the good things of doing trials in chronic patients is you have an accurate baseline. So if you, you know, with all neuroprotective strategies, you're battling with spontaneous improvement and trying to figure out with what you did actually helped and comparing it to the natural history. For chronic injuries, for the most part, they have stable deficits. So whatever you do, if it improves them, that should be you. And if it makes them worse, that's also probably you. So from a purely scientific point of view, it's a little easier to work in the chronic injury. And there's been excellent basic science work that preceded this by Eileen Anderson looking at human neural stem cells in mouse spinal cord injury and showing not only they survive and there's extensive migration when they're injected around the injury epicenter. That led to a phase one, two thoracic spinal cord injury trial that occurred mostly in Europe, a little bit in Canada. And there was some pretty remarkable sensory, no motor, but sensory improvements in those patients. That led to the cervical trial, which was multicenter, involved some of these people listed here, and was, involved immunosuppression. So if you're using fetal cells and it's not part of the patient, you need to immunosuppress, even if it's a spinal cord injection, to get those cells to survive. So there was a dose escalation component. These are perilesional stem cell injections, so not in the middle of the injury. So in some ways, this is kind of a higher risk procedure. You're taking the cord that's functioning right above the injury and injecting into it. So potentially a lot to lose. And so this is an example of a patient with a cervical injury. You can see where the cystic gliotic cavity is. You can see intact cord below and above. You can see this blood vessel here. This is a higher power view of this blood vessel. And this is the injection of the cells into the dorsal columns, about four millimeters below the peel surface. And it is a sort of two and a half minute injection, 70 microliters, five million cells. And what you see here is a pre-op, one day post-op, and a 12 month post-op imaging study. This is the injury epicenter. You can see a little bit of edema, mostly dorsally at the area where the injection was. You can see that there's no bad stuff going on in terms of motor weakness during that time. And you can see that that edema eventually subsides. That's an axial image. But it suggests that the cells or the fluid is being injected into the cord. And why the patients probably do okay is the target is the dorsal columns. And even above the lesion, that's a relatively silent area. So we published the results of that study in thoracic and cervical talking about safety of the injection process. We have another paper just submitted to Journal of Neurotrauma looking at efficacy issues. And the bottom line is that in many patients, we saw improvements over baseline. And they were segmental improvements. They weren't long-tracked improvements. But it was not in everybody. And when you looked at the control group versus the treated group, the improvement level didn't hit the required clinical efficacy threshold set by the sponsor prior to the initiation of the study. So what does that mean? You know, in short, they were looking for like a seven-point improvement. And what they got was five. And because of that, they kiboshed the study about halfway through, which was very disheartening for me. And certainly, you can imagine very disheartening for the patients. Because if a corporation doesn't think that's good enough to sell a product, that is very different to a patient who has a fixed deficit who gets some improvement. So that's sort of the stem cell story that we were involved in. We were also involved in three Schwann cell trials. And I'll briefly go over them. One of them was in subacute thoracic injury. These are the reasons why you might want to inject Schwann cells into the spinal cord. We have a great procedure for actually getting a biopsy and going from literally one cell to half a billion cells using mitogens. And you can transplant back that to the animal, whether it's a pig, a monkey, or a rat, get them to survive and improve neurological outcomes in both acute and chronic spinal cord injury. So after doing work, and this is work mostly by Jim Guest, upscaling what would be the dosage, we started a trial in 2015, finished, we started in 2012, we finished in 2015, published the results last year looking at subacute injuries between T3 and T11. These were the days, they had to be within 30 days of injury. We had exclusion criteria, and it was a dose escalation study involving a total of six patients. We talked about the process of expanding the cells. And this is the setup. This was not a hand injection. This was using XYZ-coordinated system and a needle and the cells and injecting it into the epicenter of the cord. We screened 39, enrolled nine, and transplanted six. And these are the MR imaging pre- and post-op. No tumors formed. We actually have five-year follow-up data on at least half of these patients. Lesion size diminished, but that might be just the natural history of a subacute swollen cord. And what we were able to conclude is that it's feasible. We had no adverse effects or serious adverse events related to the therapy, no infections, CSF leaks, or anything like that. And then in terms of improvement, basically that we had improvements in sensory function in three, short motor function in two, and a change of one Asia grade in that thoracic trial patients. And again, the results were published last year. We started a chronic trial in 2015. And we combined it with therapy, because we know that therapy alone can improve neurological outcomes in spinal cord injury. So we wanted to be very careful to have a sequence of therapy, transplant therapy, that was done the same way in all patients, so that if someone did over-therapy, we wouldn't be attributing any improvements to the therapy as opposed to the cells. We had a lesion-filling strategy. We involved both thoracic and cervical patients. You can see the cell concentration here. And this has been the recruitment to date. We've recruited six of our eight patients, and you can see them listed here. I'll show you some examples of one patient who was the first patient in the trial. You can see that post-injection, that it's difficult to see the lesion cavity. And we're actually targeting our cell dose based on a predetermined lesion volume. And we've had some improvements, not in all patients. That particular patient was 15 years out, and he had some recovery of hip flexion after that transplant. Again, nobody walking, but what appears to be some biological effect to the cells. I'm going to finish off with something that you probably don't see a lot in the neurotrauma section, but something that we're interested in, which is, how can we use SWAN cells for peripheral nerve injury? We see a lot of terrible boating accidents in Florida, being on the water. And we typically treat them in a traditional serral nerve graft fashion. But often, based on this study, you can see that sometimes we run out of nerve. So getting SWAN cells put in culture to supplement these nerve repairs is important. This is showing a graph of how long a nerve injury in the sciatic nerve it takes before you run out of donor serral nerve, even if harvested from both legs. And we've done lots of basic science work in the rat to show that transplanting SWAN cells in tubes is helpful. This is a particular patient who had a horrible sciatic nerve injury from a boat propeller accident. Under FDA approval, biopsy the ends of the sciatic nerve, which were devitalized. We took a serral nerve biopsy as well. The serral nerve was already cut from the propeller, put the nerve in culture, was able to get a highly purified population of SWAN cells, both from the sciatic nerve and the serral nerve, and eventually did or augmented traditional serral nerve repair of that 8 centimeter lesion with the patient's own autologous SWAN cells. This is an ultrasound showing connectivity of this mid-thigh injury. And this is just showing how long it took for her to get any recovery. You can see the dog here helping her out. This was the first time she noticed any plantar flexion of her foot, 15 months post-injury. Yes, it is. Yeah. So 15 months post-injury. And that makes sense given the long length that these nerves have to traverse to hit the gastrocnemius. Within 18 months, or only three months later, you can see that she's gotten a lot stronger. And she's gotten a little bit of dorsiflexion recovery as well. This was also a propeller blade that cut her nerve. So those are some of the clinical trials. We have a rich relationship with biomedical engineering, looking at body-machine interface training, robotic upper limb clinical assessments, and looking at ways to promote circuit plasticity, and a bionic ambulation center, and a hand center that is bionic. So I think we're running out of time here. I'll finish off with just saying that we sort of look in a holistic way. There's a whole segment that's dedicated towards male fertility. And there's been over 200 babies that have been born through that program. And so this is kind of just a summary of the different areas of which the Miami Project is involved in. And so this was the front cover of Sports Illustrated about five years ago, talking about the fact that he hasn't walked since his injury. But all of the great stuff that he's put together has improved the lives of others. It takes a lot of work, a lot of funding, and a lot of people, again, within the Miami Project to drive these trials. Thanks for your attention. Thank you.

Miami Project

paralysis cure

neurological research

stem cells

spinal cord injury

clinical trials

biomedical engineering