CAS,Originally Posted by CAS
Perhaps I can relate the history of ChinaSCINet and SCINetUSA. I formed ChinaSCINet in 2005 to do clinical trials of promising therapies in chronic spinal cord injury. We spent several years training all the centers to carry out standard neurological examinations and other outcome measures, prepared them to do clinical trials, and reviewed all of the most promising therapies of spinal cord injury. The money for the trials were raised in Hong Kong through the hard work of the HKSCIFund, which solicited donations from people in Hong Kong.
We reviewed all the therapies that were available at the time. For example, we considered embryonic stem cells (ESC), neural stem cells from aborted fetuses, bone marrow stem cells, olfactory ensheathing glial cells from aborted fetuses and the nose, Schwann cells, and HLA-matched umbilical cord blood mononuclear cells. We looked at all the combination therapies that have been reported to be beneficial.
For example, little convincing evidence suggested beneficial effects of fetal or embryonic stem cells that are not HLA-matched to the recipients. For example, despite the substantial experience of several of our surgeons in China in transplanting olfactory ensheathing glia, we were not convinced that the treatment was restoring motor function to patients with chronic spinal cord injury.
In some cases, the cells were simply not available. For example, I spoke to Woo Suk Hwang several times about cloning of embryonic stem cells for the trials. It turned out that he had falsified data concerning the cloning of human cells that he published. Likewise, we looked carefully at the work of Lima and the possibility of growing cells from the nasal mucosa of the person. We were not convinced that the cells could be grown routinely to treat large numbers of patients.
In 2006, we had only two sources of cells that were available in quantity and could be produced under GMP (good manufacturing practice) conditions: bone marrow stromal cells and umbilical cord blood mononuclear cells. We chose the latter for the following reasons:
1. Several independent laboratories had reported that umbilical cord blood cells improved recovery when transplanted into the spinal cord of rats and other animals after spinal cord injury.
2. Umbilical cord blood cells are available for cord blood banks that have enough units so that the cells can be HLA-matched. Cord blood has been used to treat over 20,000 patients around the world since 1988.
3. The cells could be isolated, produced, and delivered to the clinical trial centers for a reasonable cost. We chose to use Stemcyte, the world's largest and best commercial umbilical cord blood company to supply the cells.
We discovered that lithium strongly stimulates umbilical cord blood cells to proliferate (make many cells) and also to produce three neurotrophins that are known to stimulate regeneration in the spinal cord: NGF, NT-3, GDNF. In animal experiments, we found that lithium given to the animals will cause transplanted cells to proliferate and to produce neurotrophins in the spinal cord.
It is difficult to get umbilical cord blood cells for rats or mice. We consequently used the blood of newborn rats or human umbilical cord blood. These cells are immune-rejected within 2-3 weeks in rat spinal cord unless we used cyclosporin or some other kind of immunosuppressive drug. It turned out that cyclosporin or FK506 (another immunosuppressive drug) both completely blocked the effects of lithium on umbilical cord blood and the cells did not produce neurotrophins in response to lithium. Therefore, we were not able to test the combination therapy in rats.
Based on evidence that umbilical cord blood cells alone are beneficial in animal models of spinal cord injury and evidence that lithium strongly stimulates umbilical cord blood cells to produce neurotrophins known to activate regeneration in the spinal cord, we proposed to test the combination of the two therapies in the following clinical trials.
- CN100. This is an observational trial to demonstrate that the clinical trial centers can collect and deliver the data.
- CN101. This is a phase 1 trial to show the safety and feasibility of giving 6 weeks of oral lithium to patients with spinal cord injury.
- CN102A. This is a phase 2 trial to determine whether a 6-week course of oral lithium has any effect on neurological scores, pain, and spasticity in people with chronic spinal cord injury. The trial found that lithium significantly reduced neuropathic pain in people with chronic spinal cord injury.
- CN102B. This is a phase 2 trial to asses 4, 8, and 16 µliter injections of umbilical cord blood mononuclear cells to the spinal cord, then cell transplants with a single bolus of methylprednisolone (which we and others have shown to increase survival of transplanted cells), and then the cell transplants, methylprednisolone, and a 6-week course of lithium. This trial is underway in Hong Kong. We are recruiting the 20 patients needed to carry out the trial. We have also completed validating the cells for transplantation. The recruitment of patients for the trial is turning out to be slower than expected. However, we have recently made some changes in the protocol that may speed up recruitment. Furthermore, we have received word that the trial has been approved in China. We are working hard now to get the trial going in China in parallel with the trial in Hong Kong.
- CN103. If CN102B shows that the cell implants can be safely done without any adverse effects and possibly with beneficial effects, we will go ahead to do this trial of 400 patients with chronic spinal cord injury. All the patients will receive the umbilical cord blood mononuclear cell transplants.
SCINetUSA started in February 2009. We started the U.S. network because many people in the United States had requested to go to China to participate in the clinical trials there. I thought that this was inappropriate and therefore started the trials in the U.S. It needs to be done in the United States anyway in order to get FDA approval of the therapy. Furthermore, it is just wrong that we ship Americans overseas to participate in clinical trials of therapies that are developed in the United States. Our plan is to initiate a US103 trial that would parallel CN103. In the U.S., this trial would require about 240 patients, i.e. four groups of 60 patients that receive rehabilitation alone, rehabilitation and lithium alone, rehabilitation and cell transplant alone, and rehabilitation, cell transplant, and lithium. We have held four meetings of the investigators of 8 leading spinal cord injury centers in the United States and have agreed on all aspects of the protocol except for the rehabilitation part. We are planning a meeting next week on the subject to see if we can come up with a final plan that all the centers could accept.
Regarding costs, we estimate that CN103 in China will cost about US$6 million. US103 will cost about US$24 million. We are raising the money for these trials from every source possible. One funding source that I would like to develop for clinical trials in the United States is for each family with spinal cord injury to donate $1 per day to the U.S. trials, called SCINetUSA. If people can give that much, we would be very grateful. If people give less, we would be no less grateful. If 10,000 families were to give a dollar a day, this would provide $3.65 million per year. If 100,000 families gave this amount, ti would be $36.5 million per year.
Our goal is not to test umbilical cord blood cells and lithium as the one and only therapy for spinal cord injury. It is just the first of many therapies that we hope to test in ChinaSCINet and SCINetUSA. If we show that cord blood cells and lithium improve function in people with chronic spinal cord injury and we were able to take this combination therapy through Phase 1, 2, and 3 clinical trials with $6 million over 6 years, this would not only break a record but would turn the heads of every major pharmaceutical, therapeutic, and biotech company in the world. It currently costs an average of over $1 billion to take a therapy from discovery to market.
The networks will be continuing to test the most promising therapies of chronic spinal cord injury in the coming years. The speed at which these tests will be done will increase as we gain more experience and become better funded. At the present, we are solving problems that have never been tackled before. We are breaking new trails in the jungle. This is the first time anybody, to my knowledge, has tested a combination cell transplant and drug therapy. Once this has been done once, it would be relatively straightforward to do it again with other cells and drugs.
I apologize for the length of this discourse but given the questions that you and others were asking, I am trying to clear up misunderstandings about what these two clinical trial networks are trying to accomplish. Please note that JustADollarPlease.Org is intended to support SCINetUSA.
Wise.
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