Special Scientific Advisor, ACORDA THERAPEUTICS INC
Working2Walk 2010, Wise Young
... indicated we're also doing this in india this young woman here is the main reason why i started organizing clinical trials in china ...
About Wise Young
Wise Young, a neuroscientist and chairman of Mononuclear Therapeutics, has stated that a clinical trial of umbilical cord blood mononuclear cell transplants for chronic spinal cord injury is expected to finish in 2023, after which he plans to initiate a phase three trial to seek global approval of the treatment. He has said that a prior phase two trial in Kunming, China, in which 15 out of 20 patients with chronic complete spinal cord injury recovered walking after receiving cell transplants and intensive walking therapy, was considered impossible just a few years ago. Young has also noted that the U.S. FDA has requested additional animal studies using cells from specific cord blood banks before proceeding with a U.S. trial. Young has described the "666 program" — six hours of walking therapy per day, six days a week, for six months — as essential for recovery, and has stated that patients who did not exercise did not regain bladder or bowel function. He has also discussed research into umbilical cord blood exosomes, which he says cross the blood-brain barrier to stimulate neurogenesis, and has expressed interest in initiating clinical trials of lithium for neuropathic pain. Young has emphasized the need to reduce the cost of umbilical cord blood cell therapy from about $10,000 per dose to around $100 to make it accessible globally, and has said that the goal of treatment should be to make patients "better than they were before they were injured."
Transcript (14 segments)
✨ AI-enhanced transcript with speaker attribution
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Wise Young0:53
So the question is, what can we do to restore function in spinal cord injury? In 2003, I met Suzanne Poon. At that time, I couldn't believe she was the mother of an 18- or 19-year-old man. She asked if there was any treatment for her son, and I said no. But I asked her to join me in a partnership to form a spinal cord injury network in China. We started in 2004 and launched the China Spinal Cord Injury Network in 2005. In 2006, after we trained all the centers to do clinical trials, we had to choose a therapy to test in the network. I want to tell you about the therapy we did choose and what we hope to do with it.
It turned out that the therapy we chose to test as the first therapy for the China Spinal Cord Injury Network was umbilical cord blood cells and lithium. Many people say this is Wise Young's therapy. I assure you it's not. I didn't know anything about umbilical cord blood or lithium when I started. I simply looked at all the candidates for therapies and decided that this was the most promising and the safest to carry out in a clinical trial.
First, I want to show you some pictures of rat spinal cord so you get an idea of what spinal cord injury looks like. This is a picture of a rat spinal cord that has had a laminectomy done. You can see the spinal cord is present. Then a spinal cord that's been injured with a 10-gram weight dropped 12.5 millimeters onto the spinal cord. You can see some damage. Then a spinal cord damaged with a 25-millimeter weight drop. Ten grams is very small; my pen is heavier than 10 grams. In the middle case, at the 12.5-millimeter weight drop, you can see there are still some axons running through, but an area of severe injury. Ninety percent of rats walk with that kind of lesion. This is the equivalent of an incomplete spinal cord injury. By the way, many people think in incomplete spinal cord injury you have a lot of axons. That's not true. Most people with incomplete spinal cord injuries have very few axons, probably no more than 15 to 20 percent. But an animal with a contusion injury of the middle area will recover walking with BBB scores of 12, 13, 14. But the animal injured with a 10-gram weight dropped 25 millimeters, where there are relatively few axons running across, these are all paralyzed. They may be able to move their legs a little bit, but they're not able to support weight or walk.
This is a picture of a spinal cord at 16 weeks after injury. It illustrates what most people's spinal cords look like after injury. There's an hourglass-shaped atrophy around the injury site, and a loose matrix of tissue inside the injury site. We were quite surprised to find that in 1995, when I led a group of eight leading spinal cord injury centers to do studies on contusion injury, we found that 70 percent of spinal cords injured this way have a loose matrix of tissue cells at the injury site. Many axons are growing into this matrix, but they don't seem to be going out.
How would one address that kind of injury? What should we be doing in terms of therapy? To an axon trying to grow back from its injury point to its original destination, the first area it has to cross is the injury site. This injury site is bereft of all the signals that normally tell axons where to go. It's filled with macrophages early on and later with astrocytes. When we injected cells into the spinal cord, we found that if you inject cells right into the middle, you get an island of cells surrounded by tissue that is not spinal cord, isolated from the surrounding tissue. So we began to inject the cells in the surrounding spinal cord. When we did that, we found that the cells we inject will easily migrate into the injury site and form a bridge. Here I show a graphic depiction of how we think the cells should be injected. As it turns out, the best way to inject the cells is at a 45-degree angle right into the dorsal root entry zone. This way you completely avoid any white matter tracts in the spinal cord. You don't damage anything; you only damage the lesion area just above and below the injury site. We find that in almost all cases, the cells will migrate into the injury site and form a bridge. I want to show you some pictures of that.
The next question was what cells should we use. In 2006, there were only two GMP sources of cells: bone marrow and umbilical cord blood. GMP means Good Manufacturing Practice. This means the cells are manufactured by a company or organization that knows exactly how they were manufactured and documents every aspect, so it is safe. GMP is the industry standard that should be applied to all cells. I worry a lot about people going overseas and getting cells transplanted in India, China, or the Caribbean. You don't know where these cells have been, how they've been grown, or what reagents were used. They're putting this into your spinal cord. Not a good thing. You should ask for GMP source cells. So at that time, there were only two GMP sources: umbilical cord blood and bone marrow. In terms of fetal cells, many people have been transplanting fetal cells of all types into the spinal cord, but when we looked carefully, we found there were not enough fetal tissues to allow us to do a large-scale clinical trial even in China. For example, if we wanted to find 400 aborted fetuses in China, we would not have been able to get them. Finally, embryonic stem cells: you will hear about them, but certainly in 2006 they were not available. Geron has started clinical trials with the first embryonic stem cell lines, so this is being done now, and I think it's really important.
The first thing we did was ask whether umbilical cord blood cells are well accepted by the spinal cord. We took some umbilical cord blood cells, isolated mononuclear cells, and injected them into the spinal cord. I saw two things that made me feel very favorably inclined toward umbilical cord blood cells. First, these cells don't migrate anywhere. I feel uncomfortable injecting cells into the spinal cord and then a week later finding them in the brain stem or brain. I like cells to remain where they are, like little children you put down and they don't wander all over the place. It makes me feel more comfortable. The second thing that impressed me was that umbilical cord blood cells do not evoke gliosis around them. There's no astrocytosis. In other words, the glial cells recognize these cells as if they're part of the central nervous system and are not reacting to them, which is good.
At that same time, in 2004, Wutian Wu, a wonderful spinal cord injury researcher at Hong Kong University and a close friend, reported in a paper published in the Journal of Neurotrauma in 2004 that lithium strongly stimulates axons to regenerate in the spinal cord. I said, lithium? Lithium is something used for manic depression. By the way, lithium is the most incredible, by far the cheapest drug in the world. We all have lithium in our batteries. This is the same lithium. It has been used for over 100 years to treat manic depression and has a very well-established safety profile. I said lithium regenerates the spinal cord? How is this possible? It turns out that lithium inhibits an enzyme called glycogen synthetase kinase 3 beta and increases nuclear factors called NFAT and beta-catenin to stimulate cell growth and differentiation. This has been reported and confirmed by literally hundreds of laboratories. So we applied lithium to the umbilical cord blood cells to see what they did.
We injected green umbilical cord blood cell mononuclear cells into the spinal cord around the injury site and treated the animals with lithium by injecting it subcutaneously. We compared this against saline injections. We found that when you inject lithium, two weeks later you see many more cells, shown by the green on the two sides of the spinal cord. With saline, you can barely see the cells. If you look at the injury site, the cells have migrated in and filled up all the available spaces. Finally, we measured neurotrophins in the spinal cord, particularly the expression of neurotrophin 3, glial-derived neurotrophic factor (GDNF), and nerve growth factor. They all increased significantly. These three major neurotrophins are known to stimulate regeneration. We were quite impressed that we can put these cells in, and lithium not only enhances the survival and proliferation of the cells but also causes them to produce growth factors that stimulate regeneration.
I want to briefly go over a couple of papers published between 2003 and now that report the beneficial effects of umbilical cord blood cells and lithium on animal spinal cord injury models. Since 2003, over a dozen laboratories have reported beneficial effects of umbilical cord blood cells transplanted as late as one week after spinal cord injury. I list them here. Many of these laboratories have published five or more studies. This is one of the first and most impressive studies, published in 2007 by Dasari at the University of Illinois. You can see three graphs. On the upper left are BBB scores. BBB scores were developed by Basso, Beattie, and Bresnahan. These are walking scores for rats. 21 is a rat that walks normally, 0 is unable to walk. A score of 10 is a rat that can stand but not walk. Scores greater than 10 mean the animal can walk; scores less than 10 mean it cannot. You can see a separation of the three lines: one is cyclosporine-treated, one is human umbilical cord blood cell-treated, and one is simply injured. The human umbilical cord blood cell-treated line splits off from the other two, and those rats achieved walking scores of 15 or higher, whereas the control rats were around 10. This is a remarkable improvement in walking, from an animal that can stand but not walk to one that can walk almost normally. To an untrained eye, this would look like a very good walking rat.
Dasari did two additional tests. First, he made the animals walk on a narrow wooden beam. Normal rats scamper over with no trouble, but spinal-injured rats, because they can't tell where their hind feet are, their legs slip off the edges. They put food at the end of the beam. The injured animals lose their ability to know where their feet are, and their hind legs keep slipping off. But those treated with human umbilical cord blood cells recovered significantly. The third test was one we developed in our lab. You hold the rat under the arms so its legs dangle, then brush each leg. Every time you brush, the legs go like this. This test showed very substantial improvement. I have one minute left, so I'll talk very quickly.
I want to show you one study on lithium from Wutian Wu. On the left, the first bar is animals treated without lithium, the second bar is with lithium, the third bar is with a drug called chondroitinase ABC, and the fourth is chondroitinase ABC plus lithium. Many people don't take the time to look at this paper, but the chondroitinase plus lithium group had 40 percent regeneration of the rubrospinal tract. Many people talk about 10 or 20 percent regeneration. This treatment regenerated 40 percent of a tract. This is something to write home to mom about. Wutian Wu also showed that lithium stimulates stem cells in the spinal cord.
Finally, I'm going to end here. We started the China Spinal Cord Injury Network. These are pictures of the people there. We're doing clinical trials in China. We finished CN101 and CN102. We're now doing CN102B. As soon as 102B is finished, we will start a phase 3 study, CN103. We have now started a USA network, which will test the phase 3 study in the United States. We're also doing this in India. This young woman is the main reason I started organizing clinical trials in China. When she left the United States, she asked how therapies would get from the US to China. I said clinical trials. So I started clinical trials in China. But three years ago, when I announced we're doing the China SCINet, all these Americans wanted to go to China. I thought this was not acceptable. We need to do the clinical trials in the US. So we have now started SCINet USA. Here's a picture of Suzanne Poon amongst all these other guys. She is the heart and soul of our network in China. The network and all the clinical trials are essentially funded by fundraisers in Hong Kong. I would be glad to answer any questions. Thank you for letting me go over time.
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Narrator18:53
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