can anyone tell me what is the most promising so far....

[cdurfee99]

Hello-what is the most promising avenue of research for restoration of spinal nerves? Is time of being injured a factor? What type of injury could potentially most receptive to therapies, contusion, compression, ischemic, edema, etc. I was told that ischemic injuries could be promising. Any one out there with knowledge of research got any ideas? thanks- chris durfee

[Wise Young]

Chris, I was waiting (hoping) that somebody else would answer your question. Much has happened in the past year or so that has changed the priorities of research in the field. Let me compare where we are compared to a year ago. About a year ago, I think that most scientists and the community were focussing on about four areas: IN-1, stem cell transplants, OEG cell transplants, and combination neurotrophins. Activated macrophages were beginning to show their mettle but nobody was sure what the Proneuron trial would show.

While IN-1 continues to attract a great deal of interest, enough data has come out to convince most scienists (including Martin Schwab) that Nogo is not the only axonal growth inhibitor and that chondroitin-6-sulfate proteoglycans (CSPG) are likely to play as important or perhaps even more important of a role in stopping axonal growth at the injury site. On the other hand, some data is beginnig to suggest that IN-1's actions are not merely limited to allowing cut axons to regrow but also strongly stimulate existing axons to sprout and branch, providing a different therapeutic approach and effect that could restore function. Also Strittmatter at Yale has now isolated the Nogo receptor and has shown that fragments of Nogo can block the receptor, thereby opening a door to a different class of therapies based on Nogo receptor blockers rather than an antibody to bind Nogo. This exciting new development has been picked up by Biogen who is pushing ahead on this research as fast as possible. I continue to hope that IN-1 will go into clinical trial soon (its development is now supported by Novartis).

Stem cell therapies have likewise gone in a different direction than expected. Several studies suggest that embryonic stem cells transplanted into injured spinal cords turn mostly into oligodendroglial precursor cells and astrocytes. While this is good news for remyelination, evidence that stem cell transplants promote regeneration is still quite limited. On the other hand, the surprising and important finding is that some laboratories have obtained evidence indicating that stem cells will migrate to the injury site even when you inject them into the blood stream, that adult stem cells (bone marrow) may be able to achieve this purpose, and that remote administration of stem cells may result in stem cells replacing neurons in the brain and spinal cord. In the meantime, because there are currently no other ready source of human stem cells for transplantation, clinical trials have begun using porcine stem cells.

A year ago, three independent laboratories had already reported that OEG cells will stimulate regrowth and regeneration of the spinal cord. However, most of the studies involved only small numbers of animals, partial lesions of the spinal cord, or showed morphological evidence of regeneration without significant motor recovery. In December, Almudena Ramon-Cuetas and colleagues published a major study showing that OEG transplants can restore function in some rats with transected spinal cords. Note that the treatment was not universally successful, did not produce functional recovery in all the rats, and the functional recovery was not as spectacular as one might hope for. Nevertheless, it does restore some function in transected spinal cords. The task that remains is to find a way of getting the OEG cells either from adults or fetal sources, make sure that they are effective, and then applying to clinical trials.

Several groups had reported that combination neurotrophins are more effective. The major obstacle to this approach being taken to clinical trial is finding a company that is willing to support a series of clinical trials. Unfortunately, the two companies that hold the patents to neurotrophins have more or less abandoned the neurotrophins (Amgen and Regeneron) and have turned their attention elsewhere. In the meantime, Marie Filbin found that the combination neurotrophins may be acting by increasing cAMP levels in neurons and that the key is to increase cAMP which can be accomplished by several means. For example, a drug called Rollipram can do this and this drug is already being given to humans.

By this time last year, Michal Schwartz had already reported that activated macrophages stimulates regeneration and function recovery in rats. Because nobody really understands the mechanisms by which activated macrophages stimulate growth, there was much skepticism about these results. However, in the past year, data from a number of sources have come together to support the potential beneficial effects of macrophages, as well as other inflammatory cells. To their credit, Proneuron initiate clinical trials immediately with activated macrophages and the initial results of that trial is turning out to be better than anybody could have hoped for. Melissa Holley may have been the first to show significant recovery but it is appearing that some of the other patients may also be showing some recovery. It is likely that activated macrophages will go into further clinical trial.

Also, last year Sam David and Lisa McKerracher at the Montreal Institute of Neurology had reported that they were able to stimulate regeneration in mice by inoculating them with spinal cord homogenates. Sam David had continued this work by showing that the antibodies from inoculated mice can be transferred to other rats and show similar regenerative responses. This is really exciting and this work is progressing. It may be some time before this technology will come to clinical trial because of fears that such inoculations may produce autoimmune disease in humans.

Michal Schwartz likewise has now reported that she was able to activate lymphocytes of myelin basic protein or calpaxone (a drug that has already been approved for multiple sclerosis). There is great excitement about these results that were published last month. Unfortunately, these studies were only during the first two weeks after injury. There has yet to be studies of the inoculations for chronic spinal cord injury. Again the mechanisms of such inoculations and their effects on spinal cord injury are not well understood. It is hard to predict if and when these treatments will go into clinical trial within the coming two years. I certainly hope that they will.

Last year, Larry Benowitz reported that inosine strongly stimulates growth of surviving corticospinal tracts. This molecule apparently turn on the neuurons and their growth in the brain and spinal cord. Likewise, AIT-082 (a guanosine derivative that is another nucleotide similar to inosine) had completed clinical trials in Alzheimer's disease and has already now started clinical trials. At least three centers are now involved in this trial: Ranchos Los Amigos in Downey, California, Gaylord Hospital in Connecticut, The drug can be taken orally and has been reported to stimulate stem cell proliferation.

Finally, there is the discovery that learned non-use plays a major role in suppressing neurological recovery in people with spinal cord injury. This is a critical finding and one that is likely to revolutionize rehabilitation care around the world. The concept that forced used training paradigms can restore function in as many as 40-50% of people with chronic spinal cord injury has turned a lot of heads. My hope is that such techniques will become sufficiently widespread that they will be used in most clinical trials of spinal cord injury therapies.

In summary, several therapies that we knew about a year ago continues to be developed and are close to clinical trials. This includes IN-1 and olfactory ensheathing glia for chronic spinal cord injury. Many new therapies are coming up and we should be expecting more clinical trials in the coming year.

Wise.

[Jeff]

You were waiting for one of us to answer? I used to think I was on top of the latest in research but I really felt unqualified upon considering a reply to Chris' post. By posting a mini state-of-the-cure report, such as you did, you answered questions I had about IN-1. It also showed that we keep learning more and more and more about even the most basic elements of curing SCI. The statement that "nobody really understands the mechanisms by which activated macrophages stimulate growth" was an eye-opener for me. It shows me how much room there is left for us to understand the problem and the possible solutions.

I'm convinced, now more than ever, that the mystery will be solved completely and the tools to fix it will be developed. I just wish we had the dough to make it happen sooner.

[kngtreeman]

with all that is being learned and at the rate the learning accurs.it makes the decision to try one of these things difficult.thge individule that desperatly seeks a cure.may try one thing today and somthing better is tomorrow

scott r

[etexley]

Even if we don't "fully understand the mechanisms" involved in a treatment, is that a reason to not begin its widespread use?

Like the ALS symptoms disappearing with HIV drugs, I would think it only a humanitarian practice to at least try the drugs in a clinical setting, rather than prove "why." Incidentally, will doctors begin to prescribe these drugs for ALS ??? Or will they worry about being sued?

Eric Texley

[Wise Young]

Eric,

I think that your question exposes a major obstacle to therapy development. At the present, humanitarian motivation is one of the last reasons that a treatment goes into a clinical trial. Rather, the first reason is usually whether a treatment will generate a profit that would warrant the investment in clinical trial. If it is not likely to yield a return sufficient to generate a profit, the onus for funding the clinical trial falls upon the National Institute of Health, the only other entity that can marshall the millions of dollars that are necessary for clinical trial. NIH operates through peer review. In order for a therapy to get through peer review, it must marshall very strong scientific data. Furthermore, the NIH is not currently well-funded enough to fund anything but the hottest prospects. It takes time to garner the scientific support of a clinical trial and some therapies are left by the wayside.

There is a mistakened assumption by many people that private funding such as the SCS or even CRPF can do more than fund phase 1 or small phase 2 trials. In a typical clinical trial, particularly one that includes hospitalization, most companies currently pay as much as $25,000 or more per patient. A clinical trial that involves 100 patients, for example, cannot be funded by most private organizations.

The current situation is that many promising therapies languish while efforts are made to obtain funding for clinical trials. Despite this, it is truly amazing to me how many therapies are actually getting into phase 1 or 2 clinical trials. A lot of the work is done at the level of talking at conferences, convincing business and science advisors of various companies and other organizations that a treatment is worthwhile investment.

One approach around this is to set up a clinical trial network that is funded by NIH or a combination of NIH and private sources, to test the best new therapies that come out. This is what was done by the National Cancer Institute (NCI) of NIH. In the 1970's, during the so-called "War on Cancer", they initiated these programs in many hospitals (but also at substantial cost... the NCI budget now is over $2 billion per year). As new chemotherapies come out, patients are automatically randomized to the best experimental therapies for comparison with the best standard therapies. That is what I am hoping to get NIH to do in the coming few years.


Wise.

[Wise Young]

Scott R,

One of the reasons why these forums are here is to provide the information that allow people to make choices. An informed community not only can make the choices but help influence the direction of research.

Wise.

[mk99]

It is amazing just how expensive the cost of these trials are.

Wise: Has anyone questioned why these trials have to be so huge, complicated and expensive? Is there no way to get costs down on these things? I am sure that there are enormous legal liability issues and that is a huge factor in why trials must be so big & expensive... can anything be done?

[Wise Young]

mkowalski,

I think that the era of expensive clinical trials came in the late 1980's when hospitals began to charge drug companies for all the expenses of patients who were on clinical trial. I am not quite sure exactly when all this began.

I know that NASCIS 2 (which was from 1985-1989) costed a total of about $6 million from the NIH and randomized 487 patients. This of course included the staff that was necessary to collect and analyze the data. It was already about $13,000 to $15,000 per patient.

Before that time, most clinical trials were not that expensive because the hospitalization cost of the patients in the trial could be covered by insurance while the drug company only needed to cover the cost of the therapies and collecting the data.

It was really short-sighted. When a patient was on clinical trial, even costs of treatments and hospitalization that was unrelated to the clinical trial had to be covered by the clinical trial. Of course, eventually the insurance companies and the government ended up paying for the costs through increased costs of therapies.

Several years ago, President Clinton passed a change in regulation indicating that Medicare could cover the legitimate costs that would occur anyway if there had not been a clinical trial. I haven't seen any formal analyses of the costs of clinical trial since that regulatory change was passed.

By the way, the FDA requirements for documentation of clinical trials is onerous. In fact, companies are hiring other companies to do the documentation. Every little incident must be documented... the charts must be reviewed, etc. The costs of documentation sometimes are equal to or exceeds the costs of running the trial itself.

Wise.

[etexley]

My insurance company was being payed $275.00 an hour for outpatient rehab. Typically the rehab consisted me being asked to lift arm weights with a therapy assistant.

We seem to live in a world where people bill whatever they think they can get. But that's OK, because maybe I was paying for people who could not afford it at all.

Eric Texley