Who Plans to Attend Working 2 Walk 2011 ?

[Isildur]

I've read through as many of the papers that have been listed which constitute the rationale behind umbilical cord stem cells and lithium. All the papers used the stem cells at "acute" stages, (most after 1 week following SCI). Nothing at "chronic" stages. All the studies show a very modest effect of these particular stem cells of about 2 BBB points beyond that of cyclosporin which is used to prevent rejection. Not so good. There is no evidence that lithium promotes stem cell survival in the injured cord. The Wu paper examined lithium effects on stem cell proliferation when placed into the normal spinal cord only. The second Wu paper saw no effect of lithium alone on regeneration. There was only one additonal paper on this subject which was carried out only in vitro. All of the papers are in low impact journals. This does not give me much hope at all. I wish you only the best Christopher if you should decide you want this ucbc/lithium injection. Perhaps the decompression and intense rehab would be helpful. I'm fearful this concoction will not be quite what you are looking for in regards to actual regeneration or plasticity.

But the cells Wise is using are HLA-matched (no cyclosporin, no rejection, great survivality). Is very different.

[Schmeky]

Grammy,

Your post 206 is correct. Just as Jerry Silver has pointed out, nothing has emerged that has shown "fantastic" regeneration in the chronic contused cord, to date. I have always felt the current crop of trials (established by Dr. Young) were designed to set up the trial infrastructure. I have no doubt he would love to see meaningful recovery of some type.

[GRAMMY]

But the cells Wise is using are HLA-matched (no cyclosporin, no rejection, great survivality).

All the work with both strategies (umbilical stem cells and lithium) has only been at acute stages, nothing at "chronic" which is an entirely new and different ball game. Even with HLA matching there will likely be a need for an anti-rejection drug in humans. I haven't read that cyclosporine will be given in his trials...so I don't know. But, even then, the cells must be able to survive well. I saw only a very modest improvement in walking, and the contusion model was only a moderate one, which eventually allowed the control animals to take weight bearing steps at BBB 13. The UCBSC, raised the score to only BBB15. Frequent to consistent weight supported plantar steps and frequent FL-HL coordination, to 15 which is Consistent weight supported plantar steps, consistent FL-HL coordination; and Predominant paw position during locomotion is rotated (internally or externally) when it makes initial contact with the surface as well as just before it is lifted off at the end of stance or frequent plantar stepping, consistent FL-HL coordination and occasional dorsal stepping. Very subtle improvement in foot placement was all that was achieved. In order to show than an animal model that generates a severely paralyzed state starting with a low BBB score around 1-5, your therapy has to take the animal above 13. (THAT'S A 9-12 POINT GAIN AND NOBODY HAS ACHIEVED THAT FOR WALKING AT ACUTE STAGES, LET ALONE AT CHRONIC).

If I had an acute injury tomorrow, I'd be screaming for cells what were readily available off the shelf and already FDA approved. I'd want them to be anti-inflammatory and be able to stimulate axonal sprouting. I'd also want them to not require anti-rejection medicine. Multistem makes this product. It is an adult bone marrow derived multipotential adult projenitor cell (MAPC). In fact, this product could be given in an ambulance I.V. It was published in a high impact paper. I believe, Busch et al J Neuroscience is where the article is.

Chronics are a different ball game entirely.

@Christopher, my son has sci burst fractures at C6-7-8 and L1-2.

[GRAMMY]

Grammy,

Your post 206 is correct. Just as Jerry Silver has pointed out, nothing has emerged that has shown "fantastic" regeneration in the chronic contused cord, to date. I have always felt the current crop of trials (established by Dr. Young) were designed to set up the trial infrastructure. I have no doubt he would love to see meaningful recovery of some type.

Just getting the infrastructure set up is huge! I'm anxiously awaiting along with everyone that we see meaningful recovery. It's been too long waiting and the community should be getting something soon in the coming years. I'm keeping my fingers crossed that we can get there! We just have to keep pushing forward and trying. I'm anxious to see what therapies will come forward after the 2012 meetings.

[Isildur]

All the work with both strategies (umbilical stem cells and lithium) has only been at acute stages, nothing at "chronic" which is an entirely new and different ball game. Even with HLA matching there will likely be a need for an anti-rejection drug in humans. I haven't read that cyclosporine will be given in his trials...so I don't know. But, even then, the cells must be able to survive well. I saw only a very modest improvement in walking, and the contusion model was only a moderate one, which eventually allowed the control animals to take weight bearing steps at BBB 13. The UCBSC, raised the score to only BBB15. Frequent to consistent weight supported plantar steps and frequent FL-HL coordination, to 15 which is Consistent weight supported plantar steps, consistent FL-HL coordination; and Predominant paw position during locomotion is rotated (internally or externally) when it makes initial contact with the surface as well as just before it is lifted off at the end of stance or frequent plantar stepping, consistent FL-HL coordination and occasional dorsal stepping. Very subtle improvement in foot placement was all that was achieved. In order to show than an animal model that generates a severely paralyzed state starting with a low BBB score around 1-5, your therapy has to take the animal above 13. (THAT'S A 9-12 POINT GAIN AND NOBODY HAS ACHIEVED THAT FOR WALKING AT ACUTE STAGES, LET ALONE AT CHRONIC).

The only study that I know that combine UCBC and lithium is this,
http://www.ncbi.nlm.nih.gov/pubmed/21097398
Is in acute and transection model, but the gains from 4 to 11 is very serious in my book. And they conclude that lithium improves the effect of the cells alone.

[jsilver]

Dear Isildur,

Yep, that's the only one and it's in Chinese and unavailable to my library. I tried to find it because I too was impressed with the purported BBB improvement. So we can't appraise the results. Is this too good to be true or has something substantial occurred? Does a similar effect occur after chronic injury? These are critical questions that need answering but before going to the clinic in chronically injured people, I propose that we would like to see a solid replication of the results by an independent lab and a straightforward experiment in chronically injured animals would be a no brainer.

[Isildur]

If ChinaSCInet goes as planned, we don´t need to test it in animals. Risky? maybe, but in my opinion is time to take some controled risks.

[jsilver]

So, do I gather you are OK with using humans as experimental animals? I am not. I would like to see this repeated by a reputable lab and for certain in a contusive chronic injury model. The question is, why hasn't the pre-clinical experiment been done. Seems straightforward enough.

[Isildur]

Humans always will be used to test treatments (you can´t aprove a treatment based only in animal data), and there is always a risk. But no, China SCInet is not a "humans being guinea pigs" trials.
Lithium is common used right now, so it doesn´t need any other hard work about safety. And Umbilical Cord Blood Cells have enough research behind to start a clinical trial in humans. There are works even in dogs,
http://www.ncbi.nlm.nih.gov/pubmed/17679775
http://www.ncbi.nlm.nih.gov/pubmed/21071039
http://www.ncbi.nlm.nih.gov/pubmed/19951029
http://www.ncbi.nlm.nih.gov/pubmed/21375803

If FDA and EMA aproves the phase III in US and Europe, what would be the concern?

[jsilver]

I'm not asking for much. Just a pre-clinical experiment to show at least some efficacy trying as best as we can to model the situation in humans who will get these cells and lithium. I just can't imagine this being approved without some form of animal work with the exact cocktail at the critical time post injury. All these papers you cite are showing limited results in acute injury models., except the one in Chinese that is remarkable. Lots of things change after chronic time points. My lab and that of Gregoire Courtine are revealing that there is very slow, ongoing plasticity in the spinal cord below the level of the lesion. However, the activity of these new circuits are typically inhibited by the perineuronal net proteoglycans or perhaps other inhibitory mechanisms. If one stimulates these newly formed circuits within the spinal cord to come alive at chronic stages (we use channel rhodopsin and light stimulation in our respiratory model and Gregoire uses quipazine and a treadmill) the resulting activity can be quite robust but unfortunately horribly chaotic. We can help fix the chaos with chondrotinase . So I fear that if this therapy works to bring about significant regeneration or plasticity which can activate these circuits then the output may be far worse than paralysis. Also, after a full year the scar around the lesion is extremely dense and there are no additional measures being taken to break down scar in order to allow for the stem cells to integrate within the chronically injured cord. Thirdly, over time neurons that are axotomized tend to atrophy although fortunately they don't die. they may need to be re-awaked first before they can be asked to regenerate. And who knows what lithium may do at chronic stages? If the regulatory agencies do not have the wisdom to proceed cautiously then all we have left is prayer that we do no more harm to an already traumatized individual. By the way have you read about the potential fatal toxic effects of lithium. This is a powerful anti-psychotic.