Dr Wise Young speaks about Spinal Injury & Cord Blood

[Wise Young]

Originally Posted by paolocipolla

Wise,

recently you seemed to me less optimistic about a cure so I was wondering if you still believe this below.

It’s achievable not just within our lifetime, but within a few years,” said Young. “I believe we can fix a person enough so that someone who doesn’t know them wouldn’t know that that person has a spinal cord injury. To me that’s a cure!”

Paolo

Paolo,

I am not sure why you think that I have been less optimistic now. I continue to believe that the trials that we are doing will yield positive results and that should be within a few years. On the other hand, I have always said that the clinical trials may show negative results and that we will continue to work to identify better therapies regardless of the results of the trials. These two messages are not contradictory. In fact, they must co-exist.

Wise.

[BSgimp]

Originally Posted by paolocipolla

Wise,

recently you seemed to me less optimistic about a cure so I was wondering if you still believe this below.

It’s achievable not just within our lifetime, but within a few years,” said Young. “I believe we can fix a person enough so that someone who doesn’t know them wouldn’t know that that person has a spinal cord injury. To me that’s a cure!”

Paolo

Hello Paolo.

I was just curious what is your take on everything thats going on right now with China trials and Ch'ase going to trials. I noticed you take a part every single statement that you feel is not backed up by solid evidence. I like that about you. I think being skeptical is definitely very important. It seems that every time you question something I learn something new either from you or Dr.Wise response to your concerns. I also think it is important to stay positive.

Anyway, tell if you dont mind. What is your opinion on the "cure" in near future. Please be honest I would love to know what you think.

[Marcus]

Doctor Young, go ahead with your human trial that most of us are with you do not matter the results . For ever.

[Wise Young]

Originally Posted by Marcus

Doctor Young, go ahead with your human trial that most of us are with you do not matter the results . For ever.

Marcus, thank you very much. We will do our very best and will continue to work as hard as possible to find the therapies. Wise.

[CarlBarnardo]

Wise, you`re a legend mate - you have no idea how much everyone here appreciates what you have have done for SCI!! Thank u and stay frosty - Carl

[Wise Young]

Originally Posted by CarlBarnardo

Wise, you`re a legend mate - you have no idea how much everyone here appreciates what you have have done for SCI!! Thank u and stay frosty - Carl

Thank you for your comments. While I have presented the overall framework of our efforts with ChinaSCINet and now SCINetUSA, SCINetNorway, and SCINetIndia to test chronic spinal cord injury (SCI) therapies in many Open Houses over the last five years, comments and questions by many people here suggest that they may not have heard my talks or understood them. So, let me try to provide the rationale for our clinical trials. I am going to type it straight out without taking the time to put in references and as I would give the talk. I can add references in later.

We are doing clinical trials to assess the most promising therapies for chronic SCI. This is the main mission of ChinaSCINet, SCINetUSA, SCINetNorway, SCINetIndia, and others. I sincerely hope that many others will do trials to test therapies for chronic SCI. For decades, I have watched clinical trials exclude people with chronic SCI. Excuses include pessimism that anything would restore function to people who have been paralyzed for such a long time, lack of data showing the treatments will work in animals with chronic spinal cord injury, and paucity of clinical trial funding forcing clinicians to piggyback cell transplant procedures on surgeries that are carried out early after injury. Rather than to succumb to these excuses, we started ChinaSCINet and now SCINetUSA, SCINetNorway, SCINetIndia, and others to focus specifically on therapies for chronic SCI.

Chronic SCI is an important target for clinical trials for several reasons. First, a vast majority of people with SCI are chronic. In the United States, for example, chronic SCI outnumber acute SCI by a factor of 25x or more. Every year, about 12,000 people are hospitalized in the United States due to traumatic SCI. Over 300,000 people are severely disabled due to chronic SCI. As spinal cord injury care improves and more people survive to live nearly normal lifespans with spinal cord injury, the number of people with chronic SCI increases. I estimate that over 3 million people live with spinal cord injury around the world. That number is increasing.

Regenerating the spinal cord and restoring function has long been the holy grail of neuroscience. Rather than being paralyzed by fear of failure, we need to go boldly where none has gone before. As long as a therapy is reasonably safe and has a strong rationale for regenerating the spinal cord injury improving function in chronic spinal cord injury, we should take it to clinical trial. We should not be waiting for a sugar daddy to come and pay for the trials, chronic animal SCI studies that may never be done as well as we would like, and a majority of doctors to become more optimistic concerning the possibility of curing SCI.

Many animal studies have shown that the spinal cord can regenerate. We had won this battle for the hearts and minds of scientists in the 1990's, the decade that showed that the spinal cord can regenerate. Studies from Alberto Aguayo and Sam David in the 1980's had shown that spinal axons can and will grow long distances if placed in the peripheral nerve environment, generating the theory that axons can grow but something in the spinal cord inhibits regeneration. Many molecules were found to prevent regeneration in cell culture and animal studies, including Nogo and other myelin-based axonal growth inhibitors (AGI), chondroitinase-6-sulfate proteoglycans (CSPG) and other extracellular matrix proteins, and other molecules.

We know that something at the injury site, possibly the lack of guidance and cell adhesion molecules, is preventing growth. Various cell transplants, including umbilical cord blood mononuclear cells, olfactory ensheathing glia, Schwann cells, and other cells may be able to bridge the gap. In 1997, the multicenter animal spinal cord injury study (MASCIS) discovered that many axons will grow into the injury site of contused spinal cords. However, many axons may not grow out of the injury site and take the long journey back to their original destination to restore function. Antibodies against nogo, blocking the intracellular messenger that mediates the effects of nogo and CSPG on axonal growth, combination neurotrophin therapy, and increasing cAMP all seem to stimulate axons to grow long distances and restore function.

By the late 1990's, I had come to the conclusion that the answer to the impasse and paucity of clinical trials of chronic SCI therapies is to start doing such trials. We need to gather optimistic and altruistic doctors who are willing to spend the time and effort learning how to do clinical trials properly and to test therapies for chronic SCI. We were remarkably lucky to find such doctors in China in 2005. We have found like-minded doctors in United States, Norway, and India to form SCINetUSA, SCINetNorway, and SCINetIndia. I am profoundly grateful to these doctors, who are willing to give their time and energy to testing the most promising therapies for chronic SCI.

In 2006, after establishing the ChinaSCINet, we began looking for therapies that can be applied in clinical trials for chronic spinal cord injury. At that time, several cell transplant candidates had been reported to improve functional recovery in animals. These include olfactory ensheathing glia (OEG), umbilical cord blood mononuclear cells (UCBMC), Schwann cells, fetal neural stem cells, and embryonic stem cells. Of these, the only cells that had been reported by multiple independent laboratories to improve recovery in animals when applied a week or more after injury, immune-compatible, and available in sufficient quantity and quality to do clinical trials were UCBMC derived cells. Fetal cells, being allogenic (from another person), were not immune-compatible. I could not see giving people with chronic SCI long-term immunosuppression. While some laboratories had claimed that they could grow OEG from nasal mucosa and Schwann cells from peripheral nerve, few laboratories could grow these cells routinely and reliably.

So, we chose UCBMC as our first cell transplant candidate. Over a dozen independent laboratories have shown that UCBMC transplants improve function in animals when applied a week or more after spinal cord injury. At 1-2 weeks after SCI, the cells are unlikely to be improving function by preventing secondary injury, most of which is probably over by the end of the first week. We considered several other candidates but ruled them out. For example, fetal OEG (and all other fetal cells) are not immune-compatible. Autologous Schwann cells and bone marrow stromal cells have been reported to improve function when transplanted into the spinal cord but these cells must be prepared from cells obtained from the patient and few hospitals have the GMP (good manufacturing practice) and cGTP (current good tissue processing) facilities needed to process the cells.

In 2004, Yick, et al. from Hong Kong University had reported that lithium stimulates rubrospinal regeneration in hemisected rat spinal cords. I happend to be doing a sabbatical in Hong Kong in 2006 and became interested in why this drug is stimulating regeneration. As it turns out, lithium stimulates and inhibits phosphokinases and phosphatases in cells that all seem to converge to inhibit a ubiquitous enzyme called glycogen synthetase kinase (GSK) 3-beta. GSK3b normally inhibits nuclear factors that activate cell growth and proliferation genes. Therefore, lithium stimulates stem cells to grow and to produce growth factors. We found that lithium not only stimulates UCBMC but also neural stem cells to grow, proliferate, and produce neurotrophins. Incidentally, lithium also stimulates Akt or phosphokinase B, the intracellular messenger that activated mTOR and is believed to be the reason why blocking PTEN causes regeneration. Finally, we found that lithium stimulates neurogenesis by activating NFAT and WNT/beta-catenin but lithium inhibits astrogliogenesis and carcinogenesis by inhibiting STAT3. Lithium has of course been long used to treat manic depression and has a strong safety record.


Therefore, we proposed to test the combination of UCBMC and lithium therapy of chronic spinal cord injury. Specifically, we proposed to do five clinical trials in China. The first (CN100) is an observational trial where 25 centers examined a total total of 500 subjects with spinal cord injury over a period of a year. This was to identify centers that could do clinical trials and to show that ChinaSCINet can do multicenter clinical trials. The second trial (CN101) give a 6-week course of lithium to 20 subjects with chronic spinal cord injury in Hong Kong, showing that the drug is safe. The third trial (CN102A) randomized 40 subjects with chronic SCI to a 6-week course of placebo or lithium and examined them at 6 weeks, 6 months, and a year. That trial showed the lithium is safe and well-tolerated but did not improve neurological recovery. Unexpectedly, however, the trial suggested that lithium may reduce severe neuropathic pain not only during the 6-week period during which lithium was administered but the reduction of pain was present at 6 months.

We are currently doing the fourth trial (CN102B) where we are comparing three increasing doses of UCBMC combined with methylprednisolone (MP) and ltihium. These trials are still underway but the data suggests that the individual and combination therapies are safe, may stimulate white matter growth, and improve locomotor recovery in some patients. We therefore have decided to go ahead to apply for permission to do the phase III studies in China, Norway, India, and the United States. We are hoping to start the fifth trials (CN103) in mid-2013. If we are successful in getting these trials going and the combination therapy proves to improve function, it will be the first therapy that restores function to people with chronic SCI. If not, we will recommend that UCBMC and lithium not be used to treat chronic SCI and proceed to test other therapies.

Last month, we helped host a meeting in Xi'an where we brought a number of investigators and companies together to discuss the next generation of therapies to test in ChinaSCINet. At that meeting, two therapies stood out as particularly promising. One is a drug called Cethrin which has already completed phase I and II trials in U.S. and Canada. Discovered and developed by Lisa McKerracher, Cethrin is a biologic drug derived from bacterial C3 transferase with an added transport sequence. Cethrin blocks the intracellular messenger rho, which is responsible for mediating the inhibitory effects of nogo and CSPG on axonal growth. In the trial, Cethrin was placed on the dural surface. The phase II clinical trial showed that about 50% of Cethrin-treated subjects converted from "complete" ASIA A SCI to ASIA B or C incomplete SCI. The drug appears to be safe.

A second therapy that looked promising is cell type recently discovered by Mari Dezawa of Tohoku University in Japan. Called MUSE (multi-lineage stress-enduring cells), these cells are present in adults and can produce all types of cells, including neurons without the need for genetic manipulation. They express two easily defined markers (CD105 and SSEA3/4) that allow the cells to be isolated from bone marrow, fat, and other tissues. Unlike embryonic and other stem cells, they show little propensity for cancerous growth. Therefore, this would seem to be an almost idea cell for transplantation and one that we can use to create neural stem cells for transplantation into the spinal cord.

We are considering other therapies of course. These include chondroitinase ABC, Nogo antibodies, soluble Nogo receptor (NgR-Fc), and other treatments that block AGI's. We are also considering nasal mucosal OEG cells, mesenchymal stem cells, and various subpopulations of umbilical cord blood cells, including CD34+ cells, the pluripotent CD133+ cells, the very small embryonic like (VSEL) cells, and others. Whether or not UCBMC and lithium improve function in people with chronic spinal cord injury, we will continue to test the most promising therapies for chronic spinal cord injury.

I apologize for typographical errors and the lack of references but will add these over time.

Wise.

[keeping on]

Wise, thank you for the very in depth explanation. As you know, and we know, eventually something will come out of this and other trials that are starting. the trials are in progress. You have identified other potential trials, some of which, have already started,ie. cethrin. I know as a group many of us are watching and waiting. May your phase 3 trials show efficay and allow us to participate in a trial to recover.

anthony

[Extrmmxer]

Thank you Wise for your write up and your hard work.

[ineedmyelin]

With the recent loss of Dr. Carlos Lima I see even more how fortunate we are to have you Dr. Young.

Thank you for all your hard work Dr Young.

[BSgimp]

Thank you Dr. This is like food to my brain.