ChinaSCINet Update

[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]

Originally Posted by 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.

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.

[Wise Young]

Originally Posted by 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.

Joe, if you spend any time on these forums, you will hear of both positive and no effects of all these therapies. Many people from the U.S. and Europe go overseas for unproven experimental therapies. For example, I understand that Beike Biotechnology claims to be treating 2 patients per day of people with spinal cord injury for the past 5-6 years. Beike alone has treated thousands of patients. They charge between $20,000 to $40,000 for the therapy. I heard that they had revenues of US$21 million last year. You can do the arithmetic as well as I can. I don't know what percentage of foreigners (e.g. North American, Europe, India, Russia, Middle East, Australia) but suspect that more than half are from overseas. The Beike cells are not HLA-matched and they are given intravenously or intrathecally. they frequently provide physical therapies as well.

Other popular medical tourism destination that provide cells for spinal cord injuries include:

• Germany. You go to X-cells in Cologne (Germany) and pay $6000-$10,000 (I think) for them to extract some bone marrow cells. You then take the cells to some doctor or clinic nearby and the cells are then injected intravenously.
• India. Geeta Shroff in Delhi injects what she claims are embryonic stem cells intramuscularly or intrathecally. There are other clinics in Chennai and Mumbai that provide umbilical cord blood or bone marrow cells for intravenous or intrathecal administration.
• Caribbean and Mexico. Numerous clinics in Monterey (Mexico) and Caribbean are giving intravenous injections of umbilical cord blood cells. I don't think that they are HLA-matched.

There are of course some people claiming beneficial effects. Based on placebo response alone one would expect a 40% response rate. Unfortunately, what one does not hear about are all the patients who show no response to the therapy. Also, the responses that people report are generally not that impressive and usually not confirmed by medical examination.

I am not sure that I understand your question about ChinaSCINet's initial goals. Our goal has always been at the beginning and now: to carry out rigorous clinical trials to test promising therapies of spinal cord injury. The group decided to focus on umbilical cord blood cells and lithium for chronic spinal cord injury as its first therapeutic testing program. We are beginning to test other therapies, such as intradural decompression for subacute spinal cord injury.

There is interest within the ChinaSCINet investigators to study Schwann cells, olfactory ensheathing glia, Nogo antibodies, chondroitinase, and other therapies. The network has already completed phase 1 and 2 trials examining the safety and efficacy of lithium treatment of chronic spinal cord injury.

Wise.

[JoeMonte]

Dr. Young,
Thank you for the answers. I just didn't understand all of these bio-tech clinics selling a fake package of goods. As for SCINet , I was not sure if they wanted to work on new SCI's before a lot of scar tissue sets in or work on both Acutes and Chronics at the same time testing your treatments . I think the main goal is regeneration in all . I guess that is what I was looking for in a response but you have clarified intentions. I wanted to know about the clinical patients because I have traveled to china a few times for our business in the past. I know the southern part of china pretty well.I would travel their if you needed some U.S. patients and I qualified. I know they have a lot of SCI patients in china . I just wasn't sure if they were going to mix the nationalalities up of the patients. I didn't know if that had an effect on the different genes or if it was just the injury of a person . Thanks again. I wish you much success with these trials. Best Regards,
Joe

[MarkB701]

Yes, but is it really ethical to continue with these kinds of treatments??? I worry that you are playing God here.



Ok, I'm just kidding - go for it...!!! Great news, keep up with the progress.....I will quietly await my turn some year.......

[Geoman]

Originally Posted by Wise Young

The network has already completed phase 1 and 2 trials examining the safety and efficacy of lithium treatment of chronic spinal cord injury.

Wise.

Wise, would you be able to tell me if anything more is known about lithium and it's potential to help with Neuropathic Pain from this work and if Phase 3 will be looking at this further, or will this be a seperate study. If it does require a seperate study what sort of time frame are we looking at? It sure would be great to get this pain under control.

Your passion and determination are very admirable.

Clayton

[noirin's mum]

Thankyou Dr. Wise for the further clarification-my head is buzzing, am delighted with the amount of research and networking that has been done to get to this stage and just need to settle myself and wait!
P:s : I have worked as an Occupational therapist in stroke rehab for 17 years and i have never had a person from the medical profession take the time to explain something to me so detailed. THanks for making me feel i have a brain!