ChinaSCINet Update

[Wise Young]

I decided to set up a thread of posts about ChinaSCINet. I apologize in advance for the disorganized fashion of this topic. If I stop to write this in a formal way, it takes time and sometimes doesn't get posted until several days later. So, I am writing this off the cuff without a lot of editing and hoping that it makes sense.

I just returned from China and Hong Kong. Professor Kwok-Fai So and I visited Dr. Zhu Hui at the Kunming Army General Hospital. We were very impressed by their new hospital and operating facilities. I met their patients while they were doing their calisthenics in the morning. They are working very hard and doing intradural decompression on many of the patients. The good news is that they have now received formal permission from the Military go ahead with the planned clinical trial. The Department of Science and Technology of Yunnan province is providing some support for the trial. We are applying to the Ministry of Health in Beijing and of Yunnan Province for permission to import cells from the United States to the hospital for the trial. We have been assured that this permission should be provided in the next few weeks. In the meantime, we have arranged for technicians and doctors to be trained at the Chinese University of Hong Kong to learn how to process the cells and will be carrying out validation of the cells in the coming month. It is my fervent hope that they can start the surgery before the end of 2010. Most of the major obstacles have been taken care off and here is to hoping that there are no more.

The clinical trial in Hong Kong is commencing. We applied for and have received permission from the Institutional Review Boards of both HKU and CUHK to allocate patients to the treatment groups sequentially, rather than randomly. The first surgery has been tentatively scheduled for October 11. The cells are ready to go and we have completed validation of cell viability and quality. Five patients have been qualified. Several others may soon qualify. We are hoping that more people will volunteer to be screened for the trial.

Professor So and I, as well as Professors Wai San Poon and Gilbert Leung, spoke to a group of over 100 people on Sunday (August 29, 2010) in Kowloon, at a lecture hall next to the Kowloon Hospital. for over 3 hours, we spoke and answered questions about the trial. I did not do a count but I believe that over 50 people with spinal cord injury attended. There were many questions and we tried to answer all of them as honestly as we can. Below are some of my impressions concerning the meeting.

1. Professor So and I reviewed most of the published literature on the subject of umbilical cord blood cell (UCB) mononuclear cell (UCBMC) therapies and lithium therapy of spinal cord injury. We pointed out that a large body of literature has shown beneficial effects of UCBMC and lithium alone in rats. In the case of UCBMC, there are several dog studies as well. UCBMC also appear to prevent cell death and are anti-inflammatory, providing strong justification for the use of the cells in acute spinal cord injury.
   
2. Somebody asked about efficacy of the treatment in chronic animal SCI. I pointed out that we have not been able to test the combination therapy (UCBMC + lithium) because there is no such thing as HLA-matched umbilical cord blood and cyclosporin immunosuppression is necessary to assure survival of the cells for more than 3 weeks in the spinal cord. Unfortunately, cyclosporin blocked the effects of lithium in the spinal cord. On the other hand, there is ample evidence that umbilical cord blood cells or lithium alone, when given shortly after injury improves recovery. Several studies gave the human umbilical cord blood as late as 1-2 weeks after injury and still showed significant beneficial effect.
   
3. Dr. Leung and Dr. Poon talked about the surgery, pointing out that two small laminectomies above and below the injury are very unlikely to harm the spinal cord or to produce instability. However, it is essential that they can get good MRI images of the spinal cord to determine the best place to operate. As I have indicated here before, direct visual inspection of the spinal cord at the time of surgery is the safest way to inject cells into the spinal cord.
   
4. We emphasized that we will be using HLA-matched umbilical cord blood cells and that the cells are transplanted into the spinal cord. I pointed out that the reason why umbilical cord blood cells may have not been particularly effective in other places such as Shenzhen, India, and other medical tourism clinics may be because they have been injecting non-matched cells intravenously or intrathecally. In my opinion, the cells must reach and get into the spinal cord to be beneficial. If one does not use HLA-matched cells, the cells will be immune-rejected rapidly by the body. To inject non-HLA matched cells intravenously or intrathecally, as they are doing in Beike Biotech and other places, is a waste of time and money.
   
5. There was some discussion about higher cervical spinal cord injuries and lower T11-L1 (lumbosacral) injuries. Dr. Poon explained that injection of cells into the spinal cord about a C4 injury may damage the phrenic nucleus that is responsible for breathing and that risk should not be undertaken until we know more about the benefits of the treatment. I pointed out that injuries to the lower thoracolumbar cord may not benefit from cord blood cells transplants as much and that we will need neuronal replacement therapies for people with flaccid paralysis of the legs.
   
6. There were questions from people who were older than 60. The trial in Hong Kong was approved for people 18-60. [Note: We will try to get approval of the trial in the U.S. for people from 18-64.] I said to the audience that older people have a higher risk of complications from surgery. For a first trial, we did not think that this risk is worthwhile but that we are committed to test the safety of this trial in older patients after the current trial shows that it is safe in adults from 18-64. I also said that we are planning a trial in the U.S. for children ages 8-17.
   
7. One man asked repeatedly about whether or not I would help him to go to doctors in Shenzhen or other parts of China to get this therapy into patients (presumably him). I told him that we are not there to provide therapies to patients and our goal is to test therapies in credible clinical trials and to show the therapies work or do not work. If the clinical trials show that the therapies work, they will be widely adopted by doctors and will benefit many people. If the therapies don't work, we stop wasting time and resources on therapies that don't work and focus on the ones that do. He seemed quite angry that it has taken so long and that he has been waiting 6 years. I spoke to him later and will see him when I go to Hong Kong next to see if I can suggest what he can do for his condition.
   

After this "town-hall meeting", the investigators met and discussed the details of the trial. There is a lot of do in the coming weeks.

Wise.

[skeaman]

I decided to set up a thread of posts about ChinaSCINet. I apologize in advance for the disorganized fashion of this topic. If I stop to write this in a formal way, it takes time and sometimes doesn't get posted until several days later. So, I am writing this off the cuff without a lot of editing and hoping that it makes sense.

I just returned from China and Hong Kong. Professor Kwok-Fai So and I visited Dr. Zhu Hui at the Kunming Army General Hospital. We were very impressed by their new hospital and operating facilities. I met their patients while they were doing their calisthenics in the morning. They are working very hard and doing intradural decompression on many of the patients. The good news is that they have now received formal permission from the Military go ahead with the planned clinical trial. The Department of Science and Technology of Yunnan province is providing some support for the trial. We are applying to the Ministry of Health in Beijing and of Yunnan Province for permission to import cells from the United States to the hospital for the trial. We have been assured that this permission should be provided in the next few weeks. In the meantime, we have arranged for technicians and doctors to be trained at the Chinese University of Hong Kong to learn how to process the cells and will be carrying out validation of the cells in the coming month. It is my fervent hope that they can start the surgery before the end of 2010. Most of the major obstacles have been taken care off and here is to hoping that there are no more.

The clinical trial in Hong Kong is commencing. We applied for and have received permission from the Institutional Review Boards of both HKU and CUHK to allocate patients to the treatment groups sequentially, rather than randomly. The first surgery has been tentatively scheduled for October 11. The cells are ready to go and we have completed validation of cell viability and quality. Five patients have been qualified. Several others may soon qualify. We are hoping that more people will volunteer to be screened for the trial.

Professor So and I, as well as Professors Wai San Poon and Gilbert Leung, spoke to a group of over 100 people on Sunday (August 29, 2010) in Kowloon, at a lecture hall next to the Kowloon Hospital. for over 3 hours, we spoke and answered questions about the trial. I did not do a count but I believe that over 50 people with spinal cord injury attended. There were many questions and we tried to answer all of them as honestly as we can. Below are some of my impressions concerning the meeting.

1. Professor So and I reviewed most of the published literature on the subject of umbilical cord blood cell (UCB) mononuclear cell (UCBMC) therapies and lithium therapy of spinal cord injury. We pointed out that a large body of literature has shown beneficial effects of UCBMC and lithium alone in rats. In the case of UCBMC, there are several dog studies as well. UCBMC also appear to prevent cell death and are anti-inflammatory, providing strong justification for the use of the cells in acute spinal cord injury.
2. Somebody asked about efficacy of the treatment in chronic animal SCI. I pointed out that we have not been able to test the combination therapy (UCBMC + lithium) because there is no such thing as HLA-matched umbilical cord blood and cyclosporin immunosuppression is necessary to assure survival of the cells for more than 3 weeks in the spinal cord. Unfortunately, cyclosporin blocked the effects of lithium in the spinal cord. On the other hand, there is ample evidence that umbilical cord blood cells or lithium alone, when given shortly after injury improves recovery. Several studies gave the human umbilical cord blood as late as 1-2 weeks after injury and still showed significant beneficial effect.
3. Dr. Leung and Dr. Poon talked about the surgery, pointing out that two small laminectomies above and below the injury are very unlikely to harm the spinal cord or to produce instability. However, it is essential that they can get good MRI images of the spinal cord to determine the best place to operate. As I have indicated here before, direct visual inspection of the spinal cord at the time of surgery is the safest way to inject cells into the spinal cord.
4. We emphasized that we will be using HLA-matched umbilical cord blood cells and that the cells are transplanted into the spinal cord. I pointed out that the reason why umbilical cord blood cells may have not been particularly effective in other places such as Shenzhen, India, and other medical tourism clinics may be because they have been injecting non-matched cells intravenously or intrathecally. In my opinion, the cells must reach and get into the spinal cord to be beneficial. If one does not use HLA-matched cells, the cells will be immune-rejected rapidly by the body. To inject non-HLA matched cells intravenously or intrathecally, as they are doing in Beike Biotech and other places, is a waste of time and money.
5. There was some discussion about higher cervical spinal cord injuries and lower T11-L1 (lumbosacral) injuries. Dr. Poon explained that injection of cells into the spinal cord about a C4 injury may damage the phrenic nucleus that is responsible for breathing and that risk should not be undertaken until we know more about the benefits of the treatment. I pointed out that injuries to the lower thoracolumbar cord may not benefit from cord blood cells transplants as much and that we will need neuronal replacement therapies for people with flaccid paralysis of the legs.
6. There were questions from people who were older than 60. The trial in Hong Kong was approved for people 18-60. [Note: We will try to get approval of the trial in the U.S. for people from 18-64.] I said to the audience that older people have a higher risk of complications from surgery. For a first trial, we did not think that this risk is worthwhile but that we are committed to test the safety of this trial in older patients after the current trial shows that it is safe in adults from 18-64. I also said that we are planning a trial in the U.S. for children ages 8-17.
7. One man asked repeatedly about whether or not I would help him to go to doctors in Shenzhen or other parts of China to get this therapy into patients (presumably him). I told him that we are not there to provide therapies to patients and our goal is to test therapies in credible clinical trials and to show the therapies work or do not work. If the clinical trials show that the therapies work, they will be widely adopted by doctors and will benefit many people. If the therapies don't work, we stop wasting time and resources on therapies that don't work and focus on the ones that do. He seemed quite angry that it has taken so long and that he has been waiting 6 years. I spoke to him later and will see him when I go to Hong Kong next to see if I can suggest what he can do for his condition.

After this "town-hall meeting", the investigators met and discussed the details of the trial. There is a lot of do in the coming weeks.

Wise.

thank you DOC i am starting to believe in god again

[noirin's mum]

THankyou for taking the time to update us. Glad to see things are moving along, wish i could do more (other than spreading the word and fundraising) but have faith in you and your team. thankyou
p:s: kind of scary the thought of direct transplantation but i understand the reasoning , it's just that i remember dr. betz saying that to have touched Noirin,s cord surgically would have quite possibly affected her hand function. However i know it was in a different context at the time.and i supppose alot of people with SCI have metal fixation like noirin that would not allow MRI to give a clear image. Sonia.

[Scaper1]

The latter is something I worry about too, with both phrenic pacers and a ton of hardware in my neck I can't have an MRI.

In any case, thanks for the update Dr. Young! Hope is alive.

[SharonD]

Wise, you have no idea how these posts impact all of us. Thank you for this update. I will share the news with my family at the dinner table tonight!

[lepups3]

Thank you Dr. Young. My mom cried when she heard the news and for the first time in a long time they were happy tears.

[Imight]

The first surgery has been tentatively scheduled for October 11. The cells are ready to go and we have completed validation of cell viability and quality. Five patients have been qualified.

Wise.

Whoa. This is it. Breakthrough is more than overdue, so it has to work. It will be refined in decades to come, but this has to be it.

Good luck doctor. You've got this.

[Buck503]

Best of luck, Wise. Let me know if you need someone to help
inject the cells. I've never done it before, but it can't be that
difficult.

[EAK]

Great job as always Wise. Can't wait to hear about the results.

[lakboy]

All the very best Doc !! Finally hope at the end of the tunnel !

[suguo]

Thank you Dr. Young and all your colleagues. Your hard wok makes our dream come true.

[Johnnie Walked]

DOC. you the man !!

you the man whit the master plan !!

Thank you good luck and God bless you !!

[Jawaid]

Hope is alive.

[Wise Young]

THankyou for taking the time to update us. Glad to see things are moving along, wish i could do more (other than spreading the word and fundraising) but have faith in you and your team. thankyou
p:s: kind of scary the thought of direct transplantation but i understand the reasoning , it's just that i remember dr. betz saying that to have touched Noirin,s cord surgically would have quite possibly affected her hand function. However i know it was in a different context at the time.and i supppose alot of people with SCI have metal fixation like noirin that would not allow MRI to give a clear image. Sonia.

Noirin's mum,

We are proceeding very carefully. Let me explain about the surgical procedure.

In 2006, we held a consensus conference in China, using the vast experience in China regarding laminectomy and cell transplants by many of our investigators. We discuss many issues at this conference. Many investigators in our network, for example, have transplanted cells into many dozens or even hundreds of patients. We considered many factors:

• Ruling out intravenous/intrathecal injection. While some investigators believe that intravenously injected cells can "home" to the injury site, both a review of the literature and our own studies failed provide credible data of such beliefs, particularly for chronic spinal cord injury. For example, when we inject genetically labelled (GFP) cells intravenously into animals shortly after injury, we find very few if any of the cells getting into the spinal cord at the injury site. Likewise, unless a huge bolus of cells is injected, intrathecally administered cells typically accumulate at the bottom of the cauda equina and are not present in large numbers in the spinal cord. While we have not ruled out intrathecal injections all together, we decided do direct intraspinal injections of cells.
• Laminectomy vs percutaneous injection. There was initial discussion about injecting cells into the spinal cord by percutaneous injection (through the skin) with CT guidance. While many of our centers in China have CT guidance facilities, many surgeons felt that injection of the cells into the spinal cord exposed by laminectomy was much safer. CT guidance does not prevent the possibiity of the needle penetrating into a blood vessel on the surface of the spinal cord. There are many such vessels and a bleed would be devastating. The laminectomy will be small (so-called mini-laminectomy) that takes only half of a segment. Such laminectomies will fill in within several weeks and and will not pose an danger of instability to the spinal cord. These can be safely done with no risk to the spinal cord.
• Dorsal entry zone. We chose to inject into the dorsal root entry zone (DREZ), using a 45 degree angle (from vertical) injection route for the following reasons. This is the only route of entry into the spinal cord that does not cross any white matter pathways. The DREZ is also a area that neurosurgeons have operated on for many decades, to treat neuropathic pain. They would insert needles into the DREZ to coagulate and kill the neurons in that area to stop neuropathic pain. It seldom causes any loss of function. Any loss occurs, it is only loss of sensation for the specific dermatome of the injected segment and usually only on one side.
• Volume of the injection. A lot of people don't realize that a microliter (µliter) is one cubic millimeter. In rats, we typically inject 1 µliter or less into the spinal cord because the spinal cord of the rat is about 3 mm in diameter. The human spinal cord is about the thickness of your pinky finger (about 1.2 cm). In China, people like Hongyun Huang and others usually inject 35-50 µliters of cells. Geron just got approval of the FDA to inject embryonic stem cell derived progenitor cells into human spinal cord in volumes of 25 µliter. Anyway, we decided to be more cautious. In the current trial, we are first injecting 4 µliters (x4), then 8 µliters (x4), and then 16 µliters (x4). We will go forward with the higher volumes only if there are no significant neurological deficits associated with the injections of a previously smaller volume.
• Density of cell suspensions. We are injecting cell suspensions. If you really pack the cells, you can fit probably 200,000 cells in one µliter. We decided to use a more loosely packed suspension of 100,000 per µliter. This allows us to keep the cells longer in the syringe (while they are in the syringe, they have no access to oxygen).
• Fixed versus floating needles. The spinal cord pulsates, often 1-2 mm, with respiration. So, if one sticks a needle into such a moving spinal cord from a fixed device, the needle will be repeated plunged in and out of the spinal cord over 100 times during a 5 minute injection period. The only options are to inject quickly or use a floating needle. Rapid injections often result in higher pressure developing at the injection site and cells coming back out of the track. We thus decided to use the floating needle approach. We are inserting the smaller scalp vein needle (28 gauge) to a depth of 3 mm into the spinal cord at a 45 degree angle and then letting go so that the needle can rise and fall with spinal cord pulsations. We actually tried this in a monkey spinal cord and observed no histological evidence of damage in the spinal cord afterward.

The injured spinal cord is actually quite resilient if handled slowly and gently. I have seen many cases of intramedullary tumor removal from the spinal cord of children in the 1980's by Fred Epstein and know that it can be safely done with no loss of neurological function. The worst complications are due to hemorrhage and cerebrospinal fluid leak. But, if care is taken not to penetrate any blood vessels on the surface of the spinal cord and the dura is tightly closed, these risks should be negligible. It is one of the reasons why our surgeons believe that direct exposure of the spinal cord is necessary to ensure that both of these complications do not occur.

To date, most of the medical tourism clinics have been giving umbilical cord blood cells intravenously or intrathecally. They are often giving non-HLA matched cells. In my opinion, such treatments should have no or small beneficial effects on the spinal cord. Few of the cells will reach the spinal cord and the cells will be immune-rejected within weeks. Our protocol circumvents these approaches. The cells will be injected into the spinal cord above and below the injury site, at the edge of the white matter damage. In animal studies, we have shown that the cells migrate into and forms a bridge of cells across the injury site.

The upcoming trial will tell us a great deal about umbilical cord blood cells. It will be the first time that HLA-matched umbilical cord blood mononuclear cells will have been injected into the spinal cord of people with chronic spinal cord injury. If these cells are beneficial, this would provide strong rationale for going forward with a phase III study to establish the efficacy of such a treatment in large numbers of people with chronic spinal cord injury.

Some people were worried that participating in this trial would disqualify them from participating in other trials in the future. I want to assure people that this will not be the case for ChinaSCINet. We will do everything that we can to design clinical trials that will provide access to the most promising therapies for those subjects who have already participated in our trials. We have even gone to the unusual length of committing ourselves to provide the effective therapy, if one is found in the trial, to subjects that did not get that particular therapy.

Some people are worried that we don't have direct animal data supporting the beneficial effects of umbilical cord blood and lithium combination therapy. However, this situation sometimes happens. We had found that cyclosporin negates the effects of lithium on umbilical cord blood cells, blocking both the proliferative and the neurotrophin-secreting effects. Because animals must be immune-suppressed in order for the cells to survive even 2-3 weeks, this rules out out ability to study the effects of umbilical cord blood mononuclear and lithium treatment of rats with chronic spinal cord injury. In my opinion, much evidence from multiple independent laboratories have reported beneficial effects of umbilical cord blood mononuclear cell transplants.

Thousands of people are going to clinics in China, India, and Carribean, paying to get umbilical cord blood cells injected intravenously or intrathecally. The treatment in our trial should be significantly better in that the cells are HLA-matched and will be injected directly into the spinal cord. If umbilical cord blood cells are effective, they should show beneficial effects in this study. if they do not show beneficial effects or even deleterious effects, we will of course not continue onto the phase 3 trial or continue to give the therapy to children, older patients, or patients with high quadriplegia.

Wise.

[JoeMonte]

Dear Wise,
You mention thousands of people going to various clinics abroad. Have you ever seen or heard of any positive outcomes? Just wondering. The trials in China, do they comprise of patients from just china or are patients from other countries volunteering to be a part of the trial. You hear so much about acute and chronics. What is the exact goal of Sci-net in the beginning stages? I appreciate the knowledge you share with all of us. I am very new to medical science and have much to learn. Thank You.