Stem Cells in MS review

Discuss stem cells, adult and embryonic, and their therapeutic potential for MS here.

Stem Cells in MS review

Postby mrhodes40 » Thu Dec 04, 2008 2:36 pm

This medscape article authored by Karoussis and Kassis found here
http://www.medscape.com/viewarticle/563024_2
details the potential use of stem cells for MS. It discusses the different types of cells, studies that have been done, and the results. This paper is a REVIEW (IMHO the cadillac of papers- means somone looked extensively at a variety of other people's work on something) of cumulative research to date on the subject.

A logical treatment approach to enhance neuroprotective mechanisms and to induce neuroregeneration in MS is with stem-cell transplantation.[2,3] Stem cells are a diverse group of multipotent cells.


and
In the current review, the various types of stem cells, which were mainly studied in animal models, will be reviewed as a potential therapeutic approach for MS. The main and common mechanisms of action of all stem cells include induction of neuroregeneration and remyelination through the activation of resident stem cells, or production of new CNS cell lineage progenitors, paralleled by local and systemic immunomodulating effects.


I have been interested in the evolution of stem cell research. This paper is a great overview of what is going on. It's a little dense in some places but tell me what you think!
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Postby cheerleader » Thu Dec 04, 2008 2:57 pm

Hey Marie-
Need to log in or join in order to read. Any way to post some pertinent parts for us, or do you recommend we sign up?
AC
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Postby mrhodes40 » Thu Dec 04, 2008 3:56 pm

Gee, I'd sign up it's free. A lot of papers are distributed through medscape, I've been a member for years. It's a medical site but I'm pretty sure lay people can still join. I'm a nurse, but I don't think you have to be a medical person. If it turns out you do I'll do a big evaluation and paste the good parts but its many pages long........

It is written for docs
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Postby cheerleader » Fri Dec 05, 2008 12:21 pm

Thanks, Marie-
Signed up and have the paper now. (They have a "consumer" category for those of us not medically trained. ) Need to read more indepth, but from the first go thru it seems the mesenchymal and autologous stem cells have great promise for immune-modulation and neuroregeneration in MS, without any chemo. The paper mentions that more clinical studies will be forthcoming.
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Postby mrhodes40 » Sat Dec 06, 2008 10:24 am

Hi Cheer
Yes the paper is pretty thick, but it essentially boils down to the fact that the stem cell transplants with no chemo are helpful in that they are immunomodulatory and also potentially/possibly healing. The healing angle has yet to be proven in people--it works in mice with strokes, and they are useful nerves too-- again, those mice!-- but the modulatory angle appears to be real.

but geez if it modulates immunity and has a possible additional angle for recovery, and we compare that to things that wipe out your natural immunity and leave you vulnerable to all kinds of infection and cancer, which one would I want..........

One question will be how much of it would be needed to control MS; a dose every 9 months? I do not assume as some people do that it would be permanent, there's just no reason to assume that, one reason the out of country stem cell transpants are not a good idea; no one can afford one every year at those prices! But if it shows its promise then ordinary hospital clinics could do it much less expensively here.

This research can't go fast enough for me.

I keep remembering the Freedman work and his "two years out we had unexpected recovery" in his HSCT patients which they thought was nerve regeneration that was very late. That happened after a huge dose of chemo and radiation to kill the entire immune system, a horrendously physiologically stressful thing. Those poor patients had a ton of healing to do just to get back to normal (one died from the chemo part), let alone heal something delicate like the brain, yet 2 years later new physical abilities showed up.

These early stem transplants studies are not likley to be looking at people two years out so I hope the modulatory aspects are good enough to keep it alive as a treatment until some of that can potentially come to light down the road.

It's exciting research!
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Postby Cojack » Mon Dec 08, 2008 7:25 pm

It can't move fast enuf! ....Here's one today from China....kinda vague...





transplantation in progressive Multiple Sclerosis 08 December 2008

Stem Cells

Abstract

Background

Progressive multiple sclerosis (MS) is going with continuously disability and unresponsive to high dose steroid and immunomodulation. The autologous hematopoietic stem cell transplantation (ASCT) has been introduced in treatment of the forms of multiple sclerosis.

Due to hematopoitic stem cell transplantation involved two processes that are conditioning with high dose immunosuppressive agents and stem cell transfusion.

The short term outcomes (within 2 years after transplantation) do not preclude the immunosuppressant roles of conditionings, therefore the long term clinical outcomes after ASCT were evaluated for patients with progressive MS.

Methods

From Nov. 2001 to Jun. 2008, 34 patients with secondary progressive MS were treated with ASCT in our hospital. Of which, 26 patients were followed up more than 2 years till now. The median follow-up time was 40 months (3–83). There were 25 females (73.5%) and 9 males (26.5%). The median age of the patients was 36(20–51) years. Medium duration of disease was 36 months (15–156), and medium attacking interval time was 6.5 months (4–12). Peripheral blood stem cells were obtained by leukapheresis after mobilization with granulocyte colony-stimulating factor. BEAM, Tiniposide(600 mg/m2), melphalan(140mg/ m2), carmustin (300 mg/m2)and cytosine arabinoside (800 mg/m2), were administered as conditioning regimen.

Outcomes were evaluated by the expanded disability status scale (EDSS). No maintenance treatment was administered if no disease progression.

Results

No deaths occurred following the treatment. All patients were observed into two groups, active-free group and activity group. The former include neurological improvement and neurological stabilization after transplantation. The latter include activity with progression and relapse without progression after improvement.

Among 34 patients, 27 patients were in active-free group. Of twenty-one patients were with continuous neurological improvement without any active events. Median EDSS scores decreased from 6.0 (4.5–7.5) at transplantation to 2.0 (1.0–5) at last follow-up(p=0.000). Six patients remained neurological stable compared between the time of transplantation and last follow-up. There were 7 patients were in activity group. Of which, five patients had experience of neurological relapse during the follow-up period. However, the EDSS at relapse was lower than pre-transplantation, as well as the interval time between active events was longer than pre-transplantation.

The low doses steroid relieved the symptoms in clinical. It seems to back to relapse and remission phase. There are two patients experienced neurological deterioration within 7 months after transplantation and need further immnosuppression treatment. The confirmed active-free survival rate was 79.14% and progression-free survival rate was 94.12% at 83 months according to Kaplan and Meier survival curve. Median remission-lasting time reached 63 months (95%CI 52–74). It was a significant difference compared with 7 months (95%CI 6–7) of pre-transplantation (P=0.000).

We compared disease activity with attacking interval time, disease duration, patient’s age and EDSS of pre-transplantation. There is a relationship between active-free event and attacking interval time, OR=5.454, P=0.01(95% CI: 1.499 to 19.844,) and without relationship with duration of disease (OR=1.009, p=0.758), patient’s age (OR=1.136, P=0.147 and EDSS (OR=1.178, p=0.864) before transplantation.

Conclusions

ASCT with conditioning regimen of BEAM were able to improve or stabilize of neurological manifestations in most of progressive MS patients with failure of conventional therapy in long-term. The disease activitivy of post transplantation has a relationship with attacking interval time of pre-transplantation.

Juan Xu1,*, Tong Wu2, Li Su1,*, Bing Xin Ji3,* and Wu Han Hui3,*

1 Hematology, xuanwu hosipital, the Capital University of Medical Sciences, Beijing, China, 2 Beijing Daopei Hospital, Beijing, China, 3 Hematology, Xuan Wu Hospital, Capital university of medical science, Beijing

Source: Blood © 2008 by American Society of Hematology (08/12/08) :? :?

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Postby mrhodes40 » Tue Dec 09, 2008 11:13 am

COjack
great paper to find because of the long term follow up, similar to the Freedman work. It is hard to understand because the translation is not as clear as it could be; it is vague! Bottom line people did pretty well long term with 94% not progressing, though a few of those had some kind of temporary relapse. Two needed retreatment of some kind. They suggested the treatment kind of returned people to RRMS. The average EDSS dropped significantly, even in those who did relapse.

I thikn some insurance companies are evenpaying for this type of stem cell treatment. Revimmune is based on that theory; kill off the immune system, rebuild it with stem cells and voila! autoimmunity should be gone. I believe John's Hopkins has gotten some insurances to pay for the treatment.

The paper I started this thread with is suggesting we do not need the chemo part at all because we do not need to kill the immune system, just give the stem cells and it will both modulate the immune system function and maybe regenerate nerve tissue as well all by itself without killing immunity.

The stem cells are given for their own sake and what they might do for MS, rather than being given to rebuild the immune system the researchers just eliminated with chemo.

How much of the result seen in papers like the one you posted are related to the immune system elimination and how much of it is related to the newer understanding that stem cells are immunomodulating by themselves WITHOUT eliminating the immune system? If some patients had had JUST stem cells and no chemo, how would the two groups have compared?

Maybe the ones with no chemo would do better.

I am very interested in that research!

How much of how well the patients do is related to stem cells regenerating nerve tissue? And if we waited several years would those who had no chemo do better (chemo is really hard on people)? Might there be more nerve regeneration in those people?

And for goodness sake, eliminating the chemo phase of treatment would make the process less expensive too because that is the phase that requires long hospital stays, extensive monitoring, isolation to protect the person with no immune system from germs; all very expensive.

It's all very interesting
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Postby CureOrBust » Tue Dec 09, 2008 5:21 pm

I have no medical background, but is the following basically saying "we gave them a heap of drugs that 'freed' their stem cells into their peripheral blood"?
... after mobilization with granulocyte colony-stimulating factor. BEAM, Tiniposide(600 mg/m2), melphalan(140mg/ m2), carmustin (300 mg/m2)and cytosine arabinoside (800 mg/m2), were administered as conditioning regimen.


If so, then has anyone just tried this treatment on its own? (without the chemo either) i am assuming the rest of the treatment involves "simply" injecting their cultured stem cells back into their peripheral blood supply, and therefore it would just be a "numbers game" between the two? Just a thought. :?
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Postby mrhodes40 » Tue Dec 09, 2008 8:01 pm

Hi Cur-o
I asked my MD friend if neupogen could be given as a stand alone treatment to stimulate stem cells and just be an entirely endogenous (in the body) system and she said she thought it could work, as far as I know no one is doing that at all. I'm with you it is interesting as a thought!

I think the trouble might be that when the neupogen is given the number of stem cells are somewhat limited because the marrow makes all kinds of immune cells and just a few stem cells, and when it is stimulated it makes the usual percentages, not just stems.

In revimmune a shot of neupogen is enough to restart immunity which has only been rebooted, but in the other kinds of stem cell transplants where the person gets chemo and the marrow is destroyed, the stem cells are selectively filtered out and grown in the lab to expand the numbers hugely to billions so the destroyed marrow can be rebuilt with these large numbers of stem cells.

Stem cell treatments that include expanded stem cells like that are the ones that seem to have potential to offer a different kind of outcome; these stem cells in large numbers like that are immuno moduluting, and they have the potential to be regenerative as well.

As we talk of this here is another thought; revimmune uses chemo without expanded stem cells, just neupogen. The theory there is that the immune sytem needs to be rebooted and there is no need to destroy the entire immune system. Thus just neupogen, rather than prified expanded stem cells, is enough to get immunity restarted.

Then theres the stem cell transplant everyone thinks of which cojack just added a paper on above: the people's bone marrow is harvested, the stem cells are selectively filtered out and expanded in the lab while they get chemo strong enough to kill off their bone marrow leaving them with no immune system at all until the re instituted stem cells from the lab are given back to them rebiulding immunity over a few weeks.

Mark Freedman MD in Ottawa noticed that his patients who'd been treated with that type of stem cell tranplant had unexpected sudden improvements at the 2 year mark which he attributed to nerve regeneration from the stem cell part of treatment.

Then there's the type we've been talking about here which is stem cells given to people with NO chemo and no attempt to kill or alter the immune system. As the paper at the beginning of this thread describes, stem cells given to people with NO chemo at all alters and modualtes the immune system all on its own, and it may be regenerative as well.

It will be interesting to watch the long term results of these kinds of approaches and as one becomes more obviously the best.

If a good part of the success of stem cell approaches has to do with the fact that expanded numbers of stem cells are immune modulting all on their own and not so much to do with the "fact" autoimmunity has been rebooted, we may see that revimmune is less effective than approaches that DO use expanded stem cells

it'll be a long time before those comparisons are made though, if ever! interesting to think about though!
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Postby CureOrBust » Wed Dec 10, 2008 6:35 am

Mark Freedman MD in Ottawa noticed that his patients who'd been treated with that type of stem cell transplant had unexpected sudden improvements at the 2 year mark which he attributed to nerve regeneration from the stem cell part of treatment.
The other crazy thought, to push it way over the edge, but maybe, the 2yr delay is something that indicates its not the initial big dump of stem cells that caused the improvement? I don't know? :?
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Postby mrhodes40 » Wed Dec 10, 2008 10:22 am

These things are speculative, a guess even by Dr Freedman that the stem cells resulted in those late improvements is just that; a guess.

But it is an educated guess. Here is an abstract of rats with an induced stroke that were monitored with MRI while the radiolabeled stem cells migrated from the good side of the brain where they were implanted to the damaged areas
http://www.pnas.org/content/99/25/16267.abstract

During 3 weeks, cells migrated along the corpus callosum to the ventricular walls, and massively populated the borderzone of the damaged brain tissue on the hemisphere opposite to the implantation sites. Our results indicate that ES cells have high migrational dynamics, targeted to the cerebral lesion area


Another one again looking at imaging and living animals
http://stroke.ahajournals.org/cgi/conte ... t/35/4/952

NPC migrated to the site of infarct from the contraleral parenchyma, crossing the midline at 7 days. In control animals without infarcts, NPC remained at the site of administration. Intraventricular cell administration resulted in a wide distribution of cells, including the site of infarct


PEOPLE with mesenchymal stem cells after strokes here
http://www3.interscience.wiley.com/jour ... 1&SRETRY=0

Note the first sentence that I bolded; animals do get better funcitonal recovery from stem cells after stroke, that is not in debate.

Mesenchymal stem cell (MSC) transplantation improves recovery from ischemic stroke in animals. We examined the feasibility, efficacy, and safety of cell therapy using culture-expanded autologous MSCs in patients with ischemic stroke. We prospectively and randomly allocated 30 patients with cerebral infarcts within the middle cerebral arterial territory and with severe neurological deficits into one of two treatment groups: the MSC group (n = 5) received intravenous infusion of 1 × 108 autologous MSCs, whereas the control group (n = 25) did not receive MSCs. Changes in neurological deficits and improvements in function were compared between the groups for 1 year after symptom onset. Neuroimaging was performed serially in five patients from each group. Outcomes improved in MSC-treated patients compared with the control patients: the Barthel index (p = 0.011, 0.017, and 0.115 at 3, 6, and 12 months, respectively) and modified Rankin score (p = 0.076, 0.171, and 0.286 at 3, 6, and 12 months, respectively) of the MSC group improved consistently during the follow-up period. Serial evaluations showed no adverse cell-related, serological, or imaging-defined effects. In patients with severe cerebral infarcts, the intravenous infusion of autologous MSCs appears to be a feasible and safe therapy that may improve functional recovery. Ann Neurol 2005;57:874-882


people again with strokes here
http://www.neurology.org/cgi/content/abstract/55/4/565
Transplantation of cultured neuronal cells is safe in animal models and improves motor and cognitive deficits in rats with stroke. The authors studied the safety and feasibility of human neuronal cellular transplantation in patients with basal ganglia stroke and fixed motor deficits, including 12 patients (aged 44 to 75 years) with an infarct 6 months to 6 years previously (stable for at least 2 months). Serial evaluations (12 to 18 months) showed no adverse cell-related serologic or imaging-defined effects. The total European Stroke Scale score improved in six patients (3 to 10 points), with a mean improvement 2.9 points in all patients (p = 0.046). Six of 11 PET scans at 6 months showed improved fluorodeoxyglucose uptake at the implant site. Neuronal transplantation is feasible in patients with motor infarction.


So it is perfectly reasonable to assume that people with MS might gain new motor function after stem cells are recieved.

Here's a difference: in thoses stroke studies, no one was given any chemo to kill off their bone marrow, they only got stem cells, and the cells naturally migrated to the damaged brain tissue.

One thing I think that may be a problem with MS stem cell transplants with immune ablation (killing off the immune system with chemo) being able to help heal the brain is that since the person just got a ton of chemo and their bone marrow has been damaged, the stem cells are going to go there and maybe not be as much available to go to the brain.

The studies above and the many other like them clearly show that stem cells migrate aggressively to any area that is damaged, so stem cells after chemo may not have the potential to help heal brain tissue that stem cells otherwise given to people with MS might because so much damage has been done to the bone marrow.

The whole point of the paper that I started this thread to talk about was that giving MS patients stem cells, WITHOUT any chemo and without any other thing, results in the patients immune system modulating naturally towards calmer t cells and no autoimmunity; at least temporarily ( no long term studies yet), and additionally the people have an advantage of some potential brain recovery from the stem cells.

I am very excited to see where this research goes.

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