ChinaSCINet Update

[t8burst]

I wonder that too

Paolo

We need Brad Pitt or someone famous to become a para or a quad.

[Scaper1]

I keep my wish list next to my Dear Santa letters.

[Barrington314mx]

We need Brad Pitt or someone famous to become a para or a quad.

you are right. its sad to say. but sometimes the truth hurts.

imagine, bill gates, net worth... $61B. Warren buffett... $44B. Sergey and Larry of Google... $18.7B each. Mark Zuckerberg $17.5B.

as of april, there were 1153 BILLIONAIRES in the world. if they all gave up 1M, which they wouldnt ever even notice missing, that could be our X prize of 1 billion dollars.

[Schmeky]

Dr. Young,

I seldom log on any more, but I am glad you have made progress with the clinical trial infrastructure. I can't imagine the work and effort you have devoted to make this happen.

With best regards.

[Wise Young]

Paolo,

DTI does not only represent myelinated axons. It also detects bundles of unmyelinated axons. 3.0 Tesla MRI can detect structures that are <1 mm in diameter. If it does not detect such bundles at the injury site before treatment, this indicates that there were no bundles of axons (myelinated or not) that exceed a mm in diameter crossing the injury site. If, after treatment, such bundles appear, that would be strongly suggestive of regrowth of axons. Of course, if such structures correlate with sensory and motor recovery, that would be more convincing.

Wise.

Sure it is a strong argument for remyelination, maybe less strong for axon regeneration.
Unfortunatly, that I know, there is no technology available that can show an axon invivo in humans yet, so at best you have just strong arguments.

As I said before, I am very curious to see the DTI's as the study will be publisched.

Paolo

[Wise Young]

Grammy,

Yes, one would need to do a formal pathological analysis with the specific formulation that one would be using for the trial in a rodent species and a large animal species, applied in the intended dose and route to the target tissue. It would not be enough to do this in a herniated disc and it is also not clear that Seikagaku would allow anybody else to use their data for an IND.

Wise.

So, would one only run a pathalogical analyses if you're preparing to take the enzyme to clinical trial then?

http://www.seikagaku.co.jp/english/pdf/84.pdf

May 10, 2012
Seikagaku Corporation
(Securities Code: 4548)
Kaken Pharmaceutical Co., Ltd.
(Securities Code: 4521)
Seikagaku and Kaken Conclude a Basic Distributorship Agreement
for SI-6603, Indicated for Treatment of Lumbar Disc Herniation
Seikagaku Corporation (Tokyo) and Kaken Pharmaceutical Co., Ltd. (Tokyo) hereby
announce that today they have concluded a basic agreement concerning exclusive
marketing rights in Japan for SI-6603 (generic name: condoliase), indicated for treatment of
lumbar disc herniation. The companies plan to execute a final agreement at the end of 2012.
Seikagaku is conducting clinical development of SI-6603 in Japan and the U.S. In Japan,
the development is in a stage of the Phase III clinical trial. Seikagaku aims to promptly
conduct this trial so as to obtain approval in the shortest possible time.
Characteristics of SI-6603
Lumbar disc herniation is the partial protrusion of the nucleus pulposus at the core of each
intervertebral disc or the anulus fibrosus, the disc’s outer layer. The resulting pressure on
spinal nerve root causes leg pain, back pain and discomfort. SI-6603 is an enzyme named
condoliase that specifically degrades glycosaminoglycans, which are the main components
of the nucleus pulposus. The injection of SI-6603 into the intervertebral disc would cause
reduction of the pressure on the nerves, resulting in relief from pain. Because SI-6603 does
not break down proteins, it is thought to have no effect on surrounding tissues, such as
blood vessels and nerves. Furthermore, a single injection treatment with SI-6603 is
expected to be as effective as lumbar disc surgery in alleviating symptoms, which means
that patients would also be possible to reap benefits in the form of the patient’s physical load
and reduced medical costs, including surgical and hospitalization costs.

[Wise Young]

Dr. Young,

I seldom log on any more, but I am glad you have made progress with the clinical trial infrastructure. I can't imagine the work and effort you have devoted to make this happen.

With best regards.

Schmeky, you are welcome. The hard part is coming and we will do our best. Wise.

[GRAMMY]

Wise,

thanks for this long explaination. It actually confirmed what I knew about DTI and I learned some more.
If I interpret correctly the following:
Histological evidence confirmed significant decrease in myelin and oligodendrocyte presence in these areas of the spinal cord, suggesting that DTI images are sensitive reflection of not only the volume but also the quality of white matter. Kim, et al. [8, 9] at Washington University showed that DTI can predict long-term locomotor recovery in mice after graded contusion injuries. Herrara, et al. [10] pointed out that while DTI can detect demyelination, axonal damage and longitudinal diffusivity (lambda) did not always correlate.

it means that you can't decetc AXONS growing accros the injury site using a DTI as you seem to suggest in your presentation.
The change a DTI can show might be due just to remyelination of intact axons.

In any case I look forward with much interest to the publication with the DTIs.

Paolo

Paolo, I also have interest in the DTI data. MRI is inadequate to differentiate axons from any other strand of tissue in the vicinity of the lesion. We do know that Schwann cells enter cord lesions over time and remain there. They can have thin elongated processes and they are known to attract sensory axons from the adjacent roots into the core of the lesion. But these axons never get out of the lesion and if anything they may contribute to chronic pain. An MRI can't differentiate sensory fibers from axons that might have come from other sources above or below the lesion. Also even if they could MRI image possible axons in a lesion over time we couldn't just conclude that these have regenerated through and beyond the lesion. Without a specific axonal label they are not capable of being followed further within the complex environment of the cord beyond the injury cavity. That is why decades of research has gone into methodology to both anterogradely and retrogradely label truly regenerating axons. We don't know if stem cells are actually building bridges or not. So far, there is nothing in the literature that cells can do this even at acute stages or chronic stages. Cells injected into lesions have no alignment so without additional efforts to draw the axons along or push them along with something else like neurotrophins or pTEN deletion or allow them to exit the bridge with ch'ase there is no lengthy regeneration. At best you might get swirling axons inside the lesion core. So far there is very little evidence that chronically lesioned axons can continue to extend long axons once they are guided into the distal cord. Even if they could verify that axons have regenerated, they would need to re-lesion them or perform pharmacological experiments to show that regained function and have nothing else disappear. These kinds of experiments are essential to prove that these regenerating fibers are involved with return of function. Without these additional experiments to alter the regenerated axons, the evidence remains unsubstantiated. That is a critical reason why we need solid animal studies prior to using similar strategies in therapies on humans.

[Wise Young]

Paolo,

Let us examine each of the assumptions behind your far reaching conclusion that networks are not necessary:

1. You seem to be assuming that recruitment of chronic spinal cord injury patients is easy. Let me assure you that it is not. Despite substantial effort and a great deal of publicity for two years, Hong Kong University and the Chinese University of Hong Kong were not able to find more than 8 chronic ASIA A patients that had neurological levels between C5 and T11. Even in Kunming, where they operate on over 400 acute spinal cord injury cases per year and where there is no dearth of acute or chronic patients, it took over 6 months to recruit and transplant 20 chronic SCI subjects. There are many reasons why individual patients may not fulfill inclusion and exclusion criteria, are not ready or available for the trials, or are not willing to take the risk, etc. I believe that we probably should not expect any individual center anywhere in the world except China to treat and assess more than 20 patients per year.

2. The numbers of patients required for phase 3 trials are larger than you are assuming for the following reasons. First, you must have controls and multiple treatment groups. In the U.S., we will need to compare all components of a treatment against a combination before you can conclude that the combination is effective. In the case of UCBMC and lithium, this means that you need to have four treatment groups: rehabilitation only, rehabilition + lithium, rehabilitation + UCBMC, and rehabilitation + UCBMC + lithium. If you need 50 subjects per treatment group, that will require 200 subjects. Second, we must consider injury variables. So far, we are talking about only ASIA A subjects. Perhaps the treatment would work in ASIA B and C. Just including these two groups would triple the number of subjects. Third, we must consider treatment variables. For example, if we want to assess whether intensive locomotor training is necessary (the rehab alone group answers the question of sufficiency but not necessity), we would have to have UCBMC+lithium with and without locomotor training. If we want to know whether HLA-matching is necessary, i.e. compare HLA 4:6, 5:6, and 6:6 matches, a trial of 400 subjects would be required. Only a network can do trials of over 100 subjects.

3. You are assuming that chronic spinal cord injury subjects will travel and return for followup exams and therefore clinical trial centers can be located anywhere. It is a good idea and I have in fact looked into this possibility of setting up a center in one place where many people would go. I grant you that many patients may be willing to travel. If it were only the surgery, it might even be possible to do a trial where the subjects come back for followup examinations. In my experience, however, many people do not keep their promises. There are many reasons why people do not come back, not the least of which is that it is expensive and time-consuming for somebody to travel long distances for examinations. Particularly if they do not think the treatment is working, they don't come back. Each subject represents investments of over $100,000 to treat in a clinical trial and if they do not come back for followup, that investment is lost. The requirement for intensive and prolonged rehabilitation may further restrict the number of subjects. Our preliminary data suggest that if you don't engage in intensive walking training, locomotor recovery will be limited. This factor alone is likely to severely limit clinical trial tourism. Will everybody who travels to join a clinical trial be ready to give up 3 months of their lives and to return again at 6 months and a year (or more) after the treatment? Some might but I suspect that many would not be able to do it.

4. You assume that the results of a single trial center would be credible to the rest of the world. I can assure you that this is not the case. I know of many groups that have done 20-50 subject trials and showed very promising results and then cannot get their results published in the best journals. The reviewers turn down the papers and say that they don't believe. The reviewers are tantamount to saying that the investigators are lying. To be credible, particularly in controversial or first-in-human therapeutic successes, you must have multicenter phase 3 trials to convince the rest of the world that the treatment is efficaceous.

Finally, you cite Schwab and Buchli who are calling for more phase 1 and 2 proof-of-concept trials. I agree that we should have more phase 1 and 2 trials, but not at the expense of not doing phase 3 trials. Phase 3 trials are essential for proving efficacy and obtaining regulatory approval. Phase 1 and 2 trials are pre-coital, if you know what I mean. If we want therapies to be approved by the regulatory authorities, they must pass through phase 3 trials. We must do phase 3 trials if the treatments are to help people. Let me give you an example from the sports world. It would be like preparing a racing car to win all the time trials and get a good pole position but not having the funds to take the car to the final race. The phase 3 trial is not only the final race, it is the only race that counts. Multicenter trials are essential for phase 3 and networks are essential for efficient multicenter trials.

Wise.

First I want to point out once again that if you do a trial on acute SCI patients can't travel long distances and sometimes the acute therapies need to be administred in few hours.
For that reason it is convenient to have a multicenter trial to recrute the number of patients needed for the trial faster. Geron still took very long just to recrute 5 patients in a multicenter trial BTW.

When you have to do a trial on chronic SCI the recruting can be more efficent as you just select partecipants for an existing population that can travel easily to a clinic that is running the trial where ever it is.

Usually even for a stem cell transplant you stay in the hospital less than a week, then you move to a rehab center that can/should be in the same clinic, just think of a Spinal Unit.

Now if you have to do a phase I/II trial you would need from 10 to 20 patients. Let's say you are testing a combination therapy you may need 40 patients, to ck all combinations are safe and which show better indication of efficacy.

Then you move to phase III that may need 50 people per arm. (Keep in mind that with chronic SCI people you need less people as you have less variability)
Let's say you have three arms in the trial, so that requires 150 patients.

A neurosurgery team can do easily more than a patient a day.

Now think about a phase I/II why do you need more than one center to do 10/20 patients?

About phase III I think also a single center could be enough, but if you want you can team up with one or two centers to split the work (especially for the rehab).

In a recent issue of Nature by Martin E. Schwab and Anita Buchli, they say:

Instead of investing billions in one drug, let’s spread funding among smaller, proof-of-concept trials for compounds with good preclinical evidence. By focusing on well-selected populations (with tens of patients, not hundreds) and concentrating on a few centers..

http://www.spinalcordinjury-paralysi...-neurosciences

This is not exacly in line with what I think (as my focus is on chronic) but not far I would say.

Hope it makes sense what I said.

Paolo

[Wise Young]

Grammy,

I am not sure where you are getting all your conclusions from but I don't think that the published evidence supports what you seem to be saying. My comments are in red, embedded amongst your statements.

Wise.

Paolo, I also have interest in the DTI data. MRI is inadequate to differentiate axons from any other strand of tissue in the vicinity of the lesion.
@ DTI detects linear bundles of axons that are a mm or more in diameter. No other linear bundles of tissues extend over many centimeters in the spinal cord. When areas of interest are selected in white matter above or below the injury site, the DTI tracks contiguous bundles of longitudinally oriented tissues that extend for many centimeters in the spinal cord. This is what generates the images of white matter wavefronts above and below the injury site. Except for the anterior spinal artery, no other blood vessel courses longitudinally with the spinal cord for such distances. No other linear tissue bundles go through such distances in the spinal cord. They are very likely to be bundles of axons.

We do know that Schwann cells enter cord lesions over time and remain there. They can have thin elongated processes and they are known to attract sensory axons from the adjacent roots into the core of the lesion. But these axons never get out of the lesion and if anything they may contribute to chronic pain.
@ In 1989, Andrew Blight and I published a paper showing that Schwann cells enter the cord and myelinate axons in contused cat spinal cords. The multicenter animal spinal cord injury study (MASCIS) was also amongst the first to report that most contusion sites were usually not cavities (as many investigators claim) but a loose matrix of astrocytes with many axons running through them. It is not true that all these axons are sensory. Nor is it true that none of these axons grow out of the injury site. We all know that many animals and people have spontaneous recovery after injury, particularly incomplete spinal cord injury. The mechanism of such recovery may be due to regrowth and sprouting of axons. Many scientists have reported new serotonergic and catecholaminergic axons growing across the injury site. The one tract that has seldom been seen to cross injury sites is the corticospinal tract, particularly in contusion injuries which effectively eliminate the dorsal corticospinal tract in rats and mice. That is why the 2010 report by Liu, et al. that PTEN deletion markedly increased corticospinal tract regeneration galvanized the field. It is inaccurate to conclude only sensory axons grow into the contusion site and they never grow out of the injury site. Finally, the statement that axons that grow out of the contusion site cause neuropathic pain is very speculative.

An MRI can't differentiate sensory fibers from axons that might have come from other sources above or below the lesion.
@ Are you sure that this is true? The way DTI is done is that you select an area of white matter above or below the injury site. The software than find continuous oriented tissue. This leads to pictures of the people with ASIA A spinal cord injuries, where the white matter above the injury site stops above the injury site, the white matter below the injury site stops below the injury site, and there is a gap between the two wavefronts of white matter. DTI images of uninjured spinal cords never show such gaps. DTI images of incomplete injured spinal cords show some strands of white matter crossing the injury site. So, in fact, you can tell clearly whether fiber bundles are coming from above and below the injury site with DTI.

Also even if they could MRI image possible axons in a lesion over time we couldn't just conclude that these have regenerated through and beyond the lesion. Without a specific axonal label they are not capable of being followed further within the complex environment of the cord beyond the injury cavity. That is why decades of research has gone into methodology to both anterogradely and retrogradely label truly regenerating axons.
@ Are you quoting from some researcher here? This sounds exactly like what a researcher who has done nothing but histology of the spinal cord would say. It is true that when you do histology, you have to anterogradely and retrogradely label regenerating axons. Can you ask whoever wrote this whether they have ever done or even looked at a DTI image? If not, the person needs to stop pontificating on this subject or at least do it openly so that we can discuss this directly instead of using you as a conduit. I am sorry but I am having difficulty believing that you developed these biases by yourself.

We don't know if stem cells are actually building bridges or not. So far, there is nothing in the literature that cells can do this even at acute stages or chronic stages.
@ Perhaps the researcher who said this has never seen a cell bridge in the spinal cord and has not read the literature but I assure you that the above statements are false. Transplanted cells can and will form a contiguous bridge of cells across the injury site. Many researchers have reported axons growing on olfactory ensheathing glial cells, Schwann cells, and mononuclear cells transplanted into the spinal cord.

Cells injected into lesions have no alignment so without additional efforts to draw the axons along or push them along with something else like neurotrophins or pTEN deletion or allow them to exit the bridge with ch'ase there is no lengthy regeneration. At best you might get swirling axons inside the lesion core. So far there is very little evidence that chronically lesioned axons can continue to extend long axons once they are guided into the distal cord.
@ One does not have to have "aligned cells" for axons to grow on them. Bridge cells don't have to "push them along". Xu Xiaoming had earlier shown that axons will grow alacritously into a Schwann cell channel but are reluctant to grow out unless they are prompted to do so with combinations of neurotrophins. Chondroitinase seem to help. On the other hand, rivers of corticospinal tract axons grow in the spinal cord after injury of PTEN deleted animals without cell bridges, additional neurotrophins, or chondroitinase.

Even if they could verify that axons have regenerated, they would need to re-lesion them or perform pharmacological experiments to show that regained function and have nothing else disappear.
@ I disagree. If a therapy results in evidence of regeneration and recovery of function, why should we have to re-lesion the animal or person to make sure that the recovery is due to the regeneration? The re-lesioning method is fraught with problems and false negatives. Yes, I know that some people doubt that regeneration can occur but one does not need to re-lesion the animal to satisfy their doubts before taking the treatment to trial. Observations of regeneration and recovery due to a therapy in a reliable spinal cord contusion model should be sufficient rationale for taking the therapy to trial. More important, if one finds that a therapy is safe, causes new axonal bundles to cross the injury site, and this is associated with return of function, this should be sufficient for approval of the therapy for human use. In fact, one doesn't need the regeneration for approval. Recovery alone would be sufficient.

These kinds of experiments are essential to prove that these regenerating fibers are involved with return of function. Without these additional experiments to alter the regenerated axons, the evidence remains unsubstantiated. That is a critical reason why we need solid animal studies prior to using similar strategies in therapies on humans.
@ I do agree that we need to correlate the regeneration with function. That is one of the reasons why the PTEN story is currently quite weak. They have not yet shown that the rivers of regenerated corticospinal axons restore function in contused spinal cords. It is true that regeneration would not be meaningful if there is no functional improvement associated with it.

Wise.