OEG Treatment of ALS

[Wise Young]

Olfactory Ensheathing Glial Transplant Treatment of ALS
Updated 4/30/05

As many members of the CareCure Community knows, Dr. Hongyun Huang at the Chaoyang Hospital in Beijing has transplanted olfactory ensheathing glial cells obtained from the olfactory bulb of aborted human fetuses into chronically injured spinal cords of over 400 people. There has been much discussion of this treatment on this forum and you can find relevant links in a topic named Summary of topics related to Dr. Huang's OEG procedure (http://carecure.org/forum/showthread.php?t=18103). In the past year (2004-2005), Dr. Huang has transplanted olfactory ensheathing glia (OEG) into the brains and spinal cords of over 100 people with amyotrophic lateral sclerosis (ALS). ALS is a disease of motoneuron degeneration. Below, I summarize the little available information concerning OEG transplants and then comment on their possible effects or lack of effects on ALS.

ALS is usually a rapidly progressive disease. The Food and Drug Administration (FDA) have approved only one treatment for ALS: riluzole. This drug improves survival by several months. Many experimental therapies are being offered in hospitals around the world, often based on anecdotal clinical data and sparse or no animal studies. Some experimental treatments of ALS are listed in a topic named
husband with ALS (http://carecure.org/forum/showthread.php?t=19827) and a listing of recent publications on ALS and other neurodegenerative disorders can be found in a topic entitled Neurodegeneration Research Forum (
http://carecure.org/forum/forumdisplay.php?f=8). In addition, I have posted a Drug Development Page from the ALS Association that lists all the drugs that are in development for ALS See Topic in Clinical Trial Forum (http://carecure.org/forum/showthread.php?t=39761). Finally, I posted some information about bone marrow transplants in Italy and Nanjing below (http://carecure.org/).

I have received many emails and private topic requests requesting more information regarding Dr. Huang's treatment of amyotrophic lateral sclerosis with olfactory ensheathing glia transplants. The following is an example of an enquiry sent to me in a private topic and I thought that it might be helpful if I were to answer this one in public forum to initiate a discussion:

I am an ALS patient in NJ. I am very interested in Dr. Huang's OEC treatment for ALS, which was presented on May 3, 2004 at the 56th AANS annual meeting. I'm very interested in your opinion about Dr. Huang's report on ALS. I have following questions to you.

1. Is OEC transplantation safe? I understand there are risks associated with every operation; however, does OEC transplantation procedure present any particular risk? Are you aware of any complication that occurred in the patient received the OEC transplantation?
2. What's your opinion about the potential benefit of OEC transplantations for ALS patients? Do you know how OEC was transplanted in ALS patients? Is there any drug used in OEC transplantations which may not be good for ALS patients like steroids for immune suppressions?
3. Is there any information that you know from SCI patients that received OEC transplantations which could help me make decisions about going to try OEC transplantation in Beijing?
4. The OEC transplantations in Beijing started two years ago on more than 400 SCI patients so far. Is there any conclusion regarding the efficacy and safety of OEC on SCI patients?
5. I had attached some information of stem cell transplantations for ALS patients done in NanJing, China, and Italy. In all these trials including OEC transplantation, the benefit and improvement seems to occur very quickly after the operation. Could this be due to the trauma caused by the operation or the cells implanted?

As an ALS patient, time is not on my side and I won't be able to wait to make sure everything before I make a decision. The safety of the procedure is my top concern. I will really appreciate your kindness in helping me.


On May 3, 2004, Dr. Hongyun Huang and colleagues presented the following abstract at the American Association of Neurological Surgery in New Orleans. (Source: Braintalk Communities (http://brain.hastypastry.net/forums/showthread.php?t=20237))

Abstract: 2004 May 3

Preliminary Report of Olfactory Ensheathing Cell Transplantation for Amyotrophic Lateral Sclerosis (ALS)

Author(s):
Hongyun Huang, MD PhD, Beijing, , China
Hongmei Wang, BS, Beijing, , China
Zheng Gu, MD, Beijing, China
Ying Li, MD, Beijing, , China
Lin Chen, MD, Beijing, , China
Yinglun Song, MD, Beijing, , China
Wei Hao, MD, Beijing, , China
Jian Zhang, MD, Beijing, , China
Feng Zhang, MD, Beijing, China

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder for which there is no adequate treatment. We conducted a clinical trial in which transplantation of olfactory ensheathing cells (OECs) into the spinal cord of the patients with ALS was performed to determine whether transplantation is feasible, safe, and efficacious in controlling or reversing the state of deterioration.

Methods; We treated eight patients with ALS (six men and two women. Their ages ranged from 36 to 61 years (mean 49.9 years). The duration of symptoms was 1 to 7 years (mean 32 months). A total of 50 µl of OEC suspension (106) was injected into two sites of diseased spinal cord.

Results: Post procedure patients' neurological function improved or stabilized compared with their preoperative states 2 to 4 weeks and 3 to 6 months post-OEC transplant. Post procedure EMG studies revealed that spontaneous activity diminished or disappeared, the amplitude of motor unit action potential dropped remarkably and the numbers of motor unit action potential greatly increased.

Conclusion: These results suggest that OEC transplantation for ALS treatment is feasible, and safe and can be effective in controlling or reversing ALS deterioration both in 2- to 4-week and 3-to 6- months follow up post procedure.

General Comments

Dr. Huang started transplanting olfactory ensheathing glia (OEG, note that I use OEG rather than OEC or olfactory ensheathing cells) into the brains of patients with amyotrophic lateral sclerosis (ALS) last year. On a visit to Beijing last year, I saw a patient who was purported to have ALS and had just received OEG transplant. Dr. Huang told me that he had transplanted the OEG cells to the cerebral cortex and that some of the patients are showing rapid recovery (within days). In May 3, 2004, Dr. Huang reported that he had transplanted OEG cells into the spinal cord of 8 patients with ALS at the American Association of Neurological Surgery (AANS) in New Orleans. The description of patients indicated symptom duration of 1-7 years (mean 32 months), suggesting that most of the patients were already well along in their disease process. He reported those patients where he had transplanted to the spinal cord. Over the past 8 months, however, Dr. Huang was been transplanting mostly to the brains of people with ALS. He does so under local anesthesia, injecting about 1,000,0000 cells into the subcortical white matter below the motor cortex on each side. Many patients say that they feel stronger and better at several days after the transplant.

It is difficult to explain the beneficial effects of OEG transplants in people with ALS for the following reasons:
1. OEG cells do not replace motoneurons
2. In ALS, the degenerating neurons are far from the injection.
3. The recovery is too fast to be due to cell replacement


Answers to individual questions
1. Is OEC transplantation safe? I understand there are risks associated with every operation; however, does OEC transplantation procedure present any particular risk? Are you aware of any complication that occurred in the patient received the OEC transplantation?
• Surgery and fetal OEG transplants may be riskier in people with ALS than in spinal cord injury. To date, of about 400 patients with spinal cord injuries that have received OEG transplants, I understand that there have only been three mortalities, probably from unrelated causes several months after transplantation. To date (December 15, 2004), as I understand it, at least six patients with ALS have died or had significant complications after OEG transplantation. Several of these deaths may have been unrelated to the surgery but nevertheless the number of mortalities emphasizes the frailty of the people who have ALS. Many of them are older people with compromise respiration. The risk of surgery is much higher. It is for this reason that I think Dr. Huang has switched to mostly transplanting the OEG cells under local anesthesia to the brain rather than risk putting the patients under general anesthesia to operate on the spinal cord.

2. What's your opinion about the potential benefit of OEC transplantations for ALS patients? Do you know how OEC was transplanted in ALS patients? Is there any drug used in OEC transplantations which may not be good for ALS patients like steroids for immune suppressions?
• There is no empirical or theoretical evidence to suggest that fetal OEG transplants improves survival of degenerating motoneurons. Dr. Huang and his colleagues have reported rapid improvement in patients within days after transplantation of fetal OEG cells into the brain and spinal cord. If confirmed, this recovery is far too fast to be attributable to regeneration or remyelination, and there is no evidence that OEG cells can replace neurons. Transplanted OEG cells may secrete factors that increase excitability of the motor system or increase plasticity of the neurons. Dr. Huang and colleagues have not yet given immunosuppression to any patient. In animal studies to date, neonatal and adult OEG heterografts turn out to be immunogenic and are invariably ejected from rat spinal cords 3-4 weeks after transplantation. A single bolus dose of 30 mg/kg of methylprednisolone significantly improves survival of transplanted OEG cells at one week but the cells are eventually rejected. If we give daily cyclosporin (this is an immunosuppressive drug), transplanted OEG cells do survive in the spinal cord for 12 or more weeks. If we assume that a rat week is similar to a human month, this would suggest that the OEG cells might be rejected within months in non-immunosuppressed patients. Transplanted OEG cells may temporarily prevent the degenerative process. Continued OEG presence is likely to be necessary for lasting beneficial effects. However, the beneficial effects of OEG may be gone when the cells are rejected.

3. Is there any information that you know from SCI patients that received OEC transplantations which could help me make decisions about going to try OEC transplantation in Beijing?
• Dr. Huang published the results of the first 171 patients in a Chinese Medical Journal. All of the patients have spinal cord injury and received OEC transplants in Beijing from 6 months to over 32 years after injury. Ages range from 2 to over 64 years. When he first started, he simply did a wide laminectomy exposing not only the injury site but also the surrounding cord. In more recent patients, he has done small "keyhole" laminectomies above and below the injury site. In the case of ALS, he apparently transplants to the motor cortex through burr holes. In some ALS patients, he has transplanted to the spinal cord.

4. The OEC transplantations in Beijing started two years ago on over 400 SCI patients so far. Is there any conclusion regarding the efficacy and safety of OEC on SCI patients?
• To date, Dr. Huang has observed that almost all the patients recover sudomotor (sweating) activity, and many recovered 4-8 sensory dermatomes, and 1-2 motor levels with a week after transplantation. The procedure is being improved and OEG may be more effective when combined with other therapies, such as OEG transplantation, chondroitinase, nogo antibodies and receptor blockers, and neurotrophins such as brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF). The patients usually recovered four or more sensory dermatomes of sensory function within days, 1-2 levels of partial motor recovery within weeks, and slower return of thoracic trunk muscles over months. In some cases, the beneficial effects have been progressive. Although four dermatomes of sensory recovery and 1-2 levels of motor recovery are significant and real, these may not be sufficient to justify the risk of OEG transplantation for some people. In a small percentage of patients that Dr. Huang have studied with long term followup examinations, the sensory and motor improvements seem to be lasting, suggesting that OEG transplants may have lasting beneficial effects. This, however, needs to confirm with a controlled clinical trials with rigorous long-term followup. The major value of Dr. Huang's study to date is that he has shown the fetal OEG cells can be safely transplanted to spinal cord of patients with spinal cord injury and now ALS without significant loss of function.

5. I had attached some information of stem cell transplantations for ALS patients done in Nanjing, China, and Italy. In all these trials including OEC transplantation, the benefit and improvement seems to occur very quickly after the operation. Could this be due to the trauma caused by the operation or the cells implanted?.
• Thank you very much for telling me about the Nanjing trials showing rapid improvement in ALS patients who have received bone marrow transplants. Next week, I will be in Kunming China where there have been similar reports of early and rapid improvements in patients who have received Schwann cell transplants. Indeed, there appears to be a pattern of early improvement of function in patients with chronic SCI. This strongly suggests the need for a controlled clinical trial where cell culture media is injected into the spinal cord. Many studies have shown that trauma induces the spinal cord to secrete neurotrophins and other factors. That is the only explanation that I can think of at the present for the rapid recovery.

Summary
Transplantation of OEG cells to patients with SCI and ALS is an experimental procedure. Dr. Huang has transplanted OEG cells to about 400 patients with SCI and about 100 patients with ALS.

In patients with SCI, the treatment appears to improve sensory, lowering the sensory level by an average of about four dermatomes. Some patients have had partial improvement of 1-2 muscle groups below the injury site. To date, the procedure appears to be relatively safe.

In patients with ALS, the treatment may improve their strength and some patients but these effects are too rapid to be due to regeneration or replacement of neurons. Some patients report that their voice is stronger and they feel less tired. Dr. Huang has reported that these benefits are sustained for 6 or more months in some patients that he has followed up. These improvements, if true, cannot be explained by any known mechanism.

The procedure also appears to be riskier for people with ALS. For that reason, Dr. Huang has been implanting the brain into the cerebral cortex, through small openings in the skull, under only local anesthesia. Despite this precaution, perhaps 5% of the patients have died after transplantation although not all the deaths could be attributed to the surgery and could have been related to progression of the disease.

Wise.

[This message was edited by Wise Young on 04-30-05 at 09:14 PM.]

[rdco]

Dr. Young,

Thanks for all the info. Compared to the effects of ALS, how great are the potential risks of immunosuppression? Has Dr. Huang considered giving immunosuppression during and/or after the procedure?

Thanks again.

[Sue Pendleton]

Wouldn't it be fairly easy to prove whether the one drug that can add, at most, a few months to an ALS patient's life be compared to the OEG transplants?

Neither seems a long term gain but at least with the OEG there may be "boosters" that might be added to make a future "cocktail" type transplant.

[Wise Young]

I should add that since that time I have been trying to read up more about ALS and I was wrong in one respect. A subpopulation of patients of ALS does have severe motor cortex atrophy and that the disease appears to affect the cortex as well. The term "amyotrophic lateral sclerosis" indicates atrophy of the lateral columns of the spinal cord which, in humans, carry the corticospinal tracts. Thus, although the disease does affect lower motoneurons, it also affect the upper motoneurons. Dr. Huang's concept of injecting the cells into the motor cortex is perhaps not so far-fetched. http://www.aafp.org/afp/990315ap/1489.html

At the present, the only treatment that has been approved by the FDA for ALS is riluzole. This drug is believed to reduce glutamate release. The effect of riluzole is modest at best. One large study showed that 56.8% of patients treated with 100 mg of riluzole daily were alive without tracheostomy at 18 months compared to 50.4% of patients who received a placebo. A smaller study had shown better survival in patients who had the bulbar form of ALS. So, for these patients, the efficacy of available medication is minimal and OEG can help stave off progression of the disease even for a year or two, it would be better than any treatment available to date.

rdco, the effect of immunosuppression varies. Cyclosporin (CyA) and tacrolimus (FK506) are the most commonly used immunosuppressants. Both of these drugs prevent activation of lymphocytes to new infecting agents but does not eliminate existing immune responses. So, at least a short-term course of CyA has acceptable risks. Most people who get organ transplants get cyclosporin or tracrolimus for up to a year and often longer. Although tacrolimus is a more effective immunosuppresant, people who receive it have a higher incidence of post-transplant diabetes mellitus. Furthermore, while tacrolimus seems to reduce the incidence of acute organ rejection, it is not clear that it significantly improves survival of patients or grafts at one year after kidney transplantation.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=27842

In most immunosuppressive regimens that are recommended for organ transplantation, methylprednisolone or prednisone is used for the first three months. In addition, patients usually get anti-viral drugs. Patients who have a history of fungal infections (yeast infections such as candidiasis) probably should get anti-fungal drugs for 2-3 months after the transplant.
http://www.wramc.amedd.army.mil/departments/Medicine/Nephrology/sop/txp/txpmedprotocol.cfm

Not much is known about the optimal immunosuppressive protocols for cell transplants to the spinal cord and brain. In our experience, up to 14 weeks after transplantation, OEG cells are rejected from the spinal cord if we stop cyclosporin in rats. A single bolus of methylprednisolone does increase the initial survival of the cells but continued cyclosporin appears to be necessary for survival of the transplanted cells. I want to emphasize that we use neonatal OEG (from newborn rats) rather than the fetal OEG that Dr. Huang uses. It is true that younger fetal cells tend to be less immunogenic. Embryonic stem cells in particular express very low levels of major histocompatability genes, thereby endowing them with theoretical potential of initial survival without immunosuppression. Although, in theory, when the transplanted cells differentiate or produce cells that differentiate, those cells should begin expressing HLA antigens that may lead to immune rejection. However, some recent data suggest that there may be still effective but poorly understood mechanisms by which embryonic and fetal cells escape immune attack. Also, there is some data that suggest that hematopoietic stem cells may induce immune tolerance, i.e. get the body's cells to tolerate them. Some of this literature is summarized in

http://www.bioethics.gov/reports/stemcell/appendix_l.html

[rdco]

Dr. Young,

When might we get feedback on people receiving 2, or even 3 rounds of Dr. Huang's treatment?? I thought I read about that in one of the forums.

[Wise Young]

rdco,

Last year, Dr. Huang told me that he had done a second transplant to one person and suggested that he was planning to do more. I don't think that he has done many more. I am not sure why. It could be the fact that he has been very busy on new patients or patients with ALS. He has also been travelling quite a bit, giving lectures and seminars regarding the therapy. So, there is not much progress on that front to report.

Wise.

[Wise Young]

Due to the number of emails that I am receiving regarding OEG treatments of ALS, I am featuring this topic for a while for visitors to the site. Wise.

[hongyun]

I strongly need tell some things to patients with ALS who want to come for our procedure.
1. We can't guarantee that patients who will get our procedure can keep function stable forever; we even can't tell how much they can get from our procedure.
2. From our experience, some earliest patients we did treatment about one and half years still keep function stable; but some other ones only kept functional stable for 3-6 months. We only can prey for them to keep function stable as long as possible after our procedure. We can't forecast how long they can keep function stable both before and after our procedure.

Huang, Hongyun

[Bloom]

I am just learning about this procedure. How do I find out how to contact Dr. Huang to find out more about how my father who has ALS can be treated? Thank you.

Amy Bloom

[Wise Young]

Amy, that is Dr. Huang himself posting just below. If you go to the following topic, you will find much more discussion and information. The following is his address.

Hongyun Huang
Chair & Professor
Second Department of Neurosurgery
Beijing Chaoyang Hospital
Affiliated Capital University of Medical Science
8 Baijiazhuang Road
Beijing, P.R. China 100020
office: 86-10-85231762; fax: 86-10-65005359

[Wise Young]

The following is an email from a person who has a family member with ALS

My friends told me "there is a hope for your brother-in-law, since they saw CBS news last week, showing Dr. Huang in China successfully treated ALS with fetal cells ". After I told them my brother-in-law had had this treatment by Dr. Huang already, and currently he is in critical condition...", my friends encouraged me to write it out to share our experience with the others, it may help other PALS in the world.

My brother-in-law ZJ, 67 year old doctor in Shanghai, was diagnosed to have ALS in June last year after developed slurred speech. He was put on Rilutek and many other medications, but his ALS continued progressing. He was confined in a wheechair, communicated with hand writing, and got nutrition from a gastric tube in May 2004. All of us wanted to help him, hoping he can live longer and better. A ray of hope found from the web, we made every effort to contact with Dr. Huang and sent ZJ to him in June, after contacting with Jan, the first American PALS treated by Dr. Huang.

We paid the amount money as requested (about ZJ's 4 year salary)upon being admitted. ZJ and his wife GYZ (a doctor in a Shanghai Factory) stayed in the hospital, awaiting for the OEG cells. On day 10,the day before the procedure, one man came to the room, asking a cash of RMB$9,000. He said ZJ will have 3 holes tomorrow in the head, each hole will receive OEG cells with a cost of RMB$3,000, a total of RMB$9,000. GYZ gave him the money (about her 12 month salary), requested a receipt. But the answer was "no". GYZ was puzzeled and asked Dr. Huang and Ms. Gao, an incharge nurse in Dr. huang's team. The answer was "We don't give receipt for these, you can not get reimbursement anyway."

After the OEG cell transplant surgery, ZJ was successfully extubated on the same day, but was extremely irritated. He received sedation. There was no any improvement of his motion activity, and the whole condition appeared to get worse. GYZ was afraid that ZJ may not be able to be back home in Shanghai, and asked Dr. Huang if ZJ can D/C earlier than that had planed (one month after surgery). Dr. Huang agreed.

From Dr. Huang's hospital, they directly headed to Shanghaiupon. Upon arriving in Shanghai, ZJ was found to be in deep drowseness and sent to Zhong Sang Hospital by ambulance. In the ER, he was diagnosed to have severe hyponatremia with a blood Na+ of 113 (life-threatening level), a severe complication from neuro-surgery secondary to neuro-endocrine (hormone) disturbance. In addition,ZJ was also found in toxic shock secondary to pneumonia...Currently he is still in ZS hospital (ICU). He can no longer sit in a wheelchair, no longer comunicate with hand writing, and ventilated with a trach.

When the family asked Dr. Huang by e-mail: why such severe complications had happend, and left undiagnosed and untreted. Dr. Huang's reply was "your family did not give enough food through his gastric tube".

Actually, Ms. Gao, the incharge nurse of the team, said they had treated ALS with OEG cells for a total of 33 PALS by April 2004, there were 3 PLAS gone (died) soon after the surgery.

We are now in deep grief and only can continue praying for ZJ. Thanks to our frieds who adviced me to write it for all the PALS to share.

We also regret that we did not carefully consider it before letting ZJ go to Beijing for the treatment. Actually, my wife who works in a hospital in MA, had consulted a Neurologist there. I now copy it below for your reference. I have to erase his name since we have not asked his permission. But we now realize the truth of his letter, and would like to share with you, too.

Richard

(The following is a copy of a mail from a neurologist's consultation in MA, USA, in April 2004).

-------
Hi, Dear XXX:
I wish I could share in the enthusiasm; however, the details posted do not permit an informed opinion.

Most people in the field of treating patients with ALS who wish credibility for their treatments observe certain principles of protocol design, that permit readers of their results to evaluate them. Included in these are use of disease-appropriate standardized measures of outcome,and application of the measures by people who are masked to treatment status (even if it is impossible to have the patient also masked to treatment status).

Adherence to these expectations does not increase the costs to patients to any significant degree, if the treatment is surgical.

Furthermore, in the US individuals who are performing experiments on patients would be required to follow very specific protocols, with external oversight, to safeguard present and future patients, and to make sure all relevant data are made public. They would not be permitted to charge patients for treatments until they demonstrated their benefits (magnitude, range, percent of patients benefiting) and understood their risks.

I'm sorry I cannot be more encouraging with the information I have.

XXXX

[Caro6]

ANY help giving us some more time with my brother will do ! We do not have other options. Please Dr Prof Huang, could you respond to my mail I've send you about wanting to help my brother ? He desperatly needs you to confirm.
My family is in distress and patients with bulbar ALS do need to be stabilized as quickly as possible. They just don't have that much time...

Originally posted by Huang Hongyun:

I strongly need tell some things to patients with ALS who want to come for our procedure.
1. We can't guarantee that patients who will get our procedure can keep function stable forever; we even can't tell how much they can get from our procedure.
2. From our experience, some earliest patients we did treatment about one and half years still keep function stable; but some other ones only kept functional stable for 3-6 months. We only can prey for them to keep function stable as long as possible after our procedure. We can't forecast how long they can keep function stable both before and after our procedure.

Huang, Hongyun

Caro

[Caro6]

Please could anyone tell me if these transplantations in Nanjing, China and Italy are the same as these from Dr Huang in Beijing ? And could anyone give me the adress in Italy ?
Thanks!

[QUOTE]Originally posted by Wise Young:

OEG Treatment of SCI vs. ALS

[QUOTE]
5. I had attached some information of stem cell transplantations for ALS patients done in NanJing, China, and Italy. In all these trials including OEC transplantation, the benefit and improvement seems to occur very quickly after the operation. Could this be due to the trauma caused by the operation or the cells implanted?

Caro

[hongyun]

Dear Caro:
We do OEC or OEG transplantation, not stem cell transplantation. Our procedure is totally different from Nanjing and Italy.
Thanks!
Huang,Hongyun
Originally posted by Caro6:

Please could anyone tell me if these transplantations in Nanjing, China and Italy are the same as these from Dr Huang in Beijing ? And could anyone give me the adress in Italy ?
Thanks!

[QUOTE]Originally posted by Wise Young:
OEG Treatment of SCI vs. ALS

[QUOTE]
5. I had attached some information of stem cell transplantations for ALS patients done in NanJing, China, and Italy. In all these trials including OEC transplantation, the benefit and improvement seems to occur very quickly after the operation. Could this be due to the trauma caused by the operation or the cells implanted?

Caro

Huang, Hongyun

[BLU STELLINA]

Dear Caro,
this is Dr.Mazzini's mail address in Torino:MazziniI@libero.it.
Write and she will give you all informations you need.

[Wise Young]

blu stellina, thank you very much.

Caro, Letizia Mazzini is at the Department of Neurology at the University of Torino. According to a paper that she and her colleagues published in 2003 (see abstract in the Neurodegeneration forum (http://carecure.org/forum/showthread.php?t=572)), they apparently obtained bone marrow cells and grew stem cells from these cells and then injected them intrathecally into 5 patients with ALS. They pointed out that that the procedure appears to be safe and well-tolerated by ALS patients and that none of the patients got worse. They pointedly did not say that the patients got better from the therapy. Silani, et al. (2004) (http://carecure.org/forum/showthread.php?t=556) refers to the study by Letizia Mazzini and says that "stem cell therapy will need to be used with other drugs or treatments, such as antioxidants and/or infusion of trophic molecules.

Regarding the clinical trial in Nanjing, I only have indirect descriptions of the work there and their web site. According to information that KZ (the person who sent me the above question):
Additional Information of Stem Cell for ALS

Following is a translation of information regarding the transplantation found in the web site of No. 454 Hospital in Nanjing, China.
(According to the doctor I spoke to in Nanjing, about 50 to 80 ml bone marrow is drawn from hip. The volume of stem cells solution/suspension after the separation is about 1.5 ml to 2 ml. There is no regrowth of stem cell before transplantation. The detail of procedure is not available.)

The Transplantation of the Patient's Self Bone Marrow Stem Cells to Treat Motor Neuron Disease

Methods: The stem cells from the patient's bone marrow is processed and injected back into patient's central nervous system (spinal cord). The patient is also given the cell membrane stabilizer and nerve nutrition drug.

Effect: 38 cases of self bone marrow stem cells transplantation have been carried out from October 28 to December 5 in 2003; of which one failed to get in touch with us, one had no effect; three have no evident effect because the time between the transplantation and this report is too short, the rest have shown different degree of improvement in the symptom. This manifests mainly in: 1. Speaking becomes rather distinct than before transplantation. 2. Swallow has improved. 3. The power of gripping has increased. 4. The ability to stand and walk has been enhanced. These changes mostly appeared from one day to within a week after the transplantation. None of patient shows progression of symptom after transplantation. The short term curative effect is good but the long term one remains to be proved by time.

Analysis: The fact that patients start to show improvement in their symptom within one week after the transplantation indicates that the cell factors excreted by the transplanting cells have a curative effect on the motor neuron. For a patient, the stem cells existing in his bone marrow can not prevent the motor neuron disease from developing, but the same stem cells once transplanted into the central nervous system are able to have a curative effect on the motor neuron disease. This phenomenon has shown that the cell factors which are excreted by the bone marrow stem cells and provide nutrition support to the motor neuron fail to enter into the brain and spinal cord and the most likely cause of this failure is that the function of transferring these cells by the blood - brain barrier has been obstructed so that the motor neuron become gradually degenerate and die because of nutrition shortage. This cause of the motor neuron disease is what we infer from the clinical treatment, but much work remains to be done to verify this theory. A longer time observation is needed to see whether the bone marrow stem cells can grow into the motor neuron and further their curative function.

The Merits of the Self Bone Marrow Stem Cells Transplantation: It avoids two major difficulties: ethical problem and immunology repellence. Theoretically, the transplanted own stem cells can live better, propagate and differentiate in the patient's central nervous system, and can possibly have a long term curative effect.

Typical Cases:
1. Male, age 56. After transplantation the gripping power of his both hands increases by 2 kg, the muscle strength of his both lower limbs rises from 0 level to 2 level, and the symptom of his swallow difficulty has lessened.
2. Male age 68. He had difficulty in lifting his pants with both his hands before surgery. Five days after the transplantation he can raise his pants at ease and his both hands can reach the back of the body to lift the pants.
3. Male age 60. His right hand could only touch his forehead when combing his hair. Six days after transplantation, his right hand is able to touch his rear occipital.
4. Female age 54. Before the surgery, she could only make a phone call with others holding the phone for her and relieve herself with the help of her family members. But three days after the transplantation, she can call her family members with right hand holding the cell phone for several minutes and lift her own buttocks by herself when the bed pan is placed under her.
5. Male age 52. He could only turn over in bed with the help of the attendants. After the transplantation, he can do it by himself and his right hand power of gripping increases from 3kg to 9 kg.
6. Male age 54. After the transplantation, his right hand grip increases from 0 kg to 2 kg, and his speaking power is evidently increasing. And ten days after the surgery, he can put his hands into his pant pocket, which he was unable to do for more than one year.

Remarks: The goal of this trial is to prevent the further progression of the patient's condition and strive for a gradual improvement in the symptom. From the above mentioned cases we can see that the treatment has an improvement in the patients' paralysis to a different degree depending on patients own condition, but this treatment does not cure the motor neuron disease nor provide major recovery as the patient would hope in the short term. The long term effect remains to be seen.


KZ also sent me the following conference report regarding Mazzini's trial

Followings are from the conference reports regarding a similar trial by Dr. Mazzini in Italy. The abstract can be viewed using the link: http://www.mndassociation.org/downloads/milan/Session_4b.pdf

14th International Symposium on ALS/MND in Nov. 2003
...controversy and surprise
There was also a presentation on a study to determine the safety and tolerability of stem cells in MND.

Following the recent publication of Dr Mazzini's paper on a study to investigate the feasibility and safety of administering stem cells to people with MND, Dr Mazzini gave an update on her research in the clinical trials session on the Symposium. From the seven patients that have received stem cells to date Mazzini and colleagues concluded that, " Our results appear to demonstrate that... transplantation of these (stem) cells into the spinal cord of humans are safe and well tolerated by ALS patients".
As in clinical studies of potential drugs, Dr Mazzini used several standard tests for muscle strength and respiratory function to monitor progress during the study. Data from these measures up to 21 months after and six months prior to receiving additional stem cells were presented. All the patients are still alive, although both muscle strength and respiratory function are declining. One interpretation of the data is that the patients are declining at a slower rate after receiving the additional stem cells. In such a small group of patients, with no controls, it is difficult to say whether any differences in the rate of decline of muscle strength or in respiratory function would be due to the stem cell treatment or to the natural progression of the disease in these individuals. In addition to the clinical study, Dr Mazzini briefly mentioned a study in progress in animal models of MND.

Dr Mazzini's presentation evoked some robust debate on both the methodology and ethics of conducting such controversial studies. Several eminent clinicians voiced strong concerns about Dr Mazzini's clinical stem cell studies. These echoed Prof Michael Swash's caution in an editorial of the journal in which this study was published " it is inappropriate, in the present state of knowledge, to use stem cells as a therapy in ALS ".

In the closing session of the Symposium Dr Lucie Bruijn, Science Director and Vice President of ALS Association, named three drugs that may be beneficial in MND. Promethazine, Ebselen and Cetriaxone were identified as a result of a large screening programme in which 75% of the drugs licensed by the FDA were investigated. These drugs were found to have some beneficial effects in two or more laboratory assays and were studied further in SOD1 mice. These animal experiments are in progress and Dr Bruijn commented that a report is being written for publication next year.

Although two of these drugs are licensed for other indications in the UK, it should be stressed that these are very preliminary studies on their possible, beneficial effects for MND.

13th International Symposium on ALS/MND

Initial Findings and Concerns Raised
At the 13th International Symposium on ALS/MND held November 17-19, 2002 in Melbourne, Australia,
L. Mazzini, MD, and colleagues from Italy reported initial results (6-month) from a pilot clinical trial using stem cells.

The study presentation raised a number of questions and criticisms of the study design and methods from the researchers and clinicians present. Serious concerns from the scientists in the audience include:
1. There was no scientific basis offered as rationale to conduct the study.
2. It is doubtful that the 1.5 milliliters of stem cells were actually injected, as this volume is very large for the space of the spinal cord.
3. There is not clear evidence that the small change in proximal muscle strength reported can be attributed to an effect of the stem cells. It is not certain that the stem cells actually were delivered into the spinal cord. Other variables, such as the trauma of the injection, could account for the muscle function changes.

As reported by Mazzini, the aims of this 12-month study-still in process-are to:
1. Verify the safety and tolerability of injecting autologous mesenchymal stem cells into the spinal cord
2. Examine the effects of the injection of stem cells, and
3. Evaluate the impact of the stem cell injection on quality of life

In this trial of a small number of people with ALS, bone marrow was collected from each patient (autologous) and the mesenchymal stem cells were extracted and later injected into the patient's spinal column. Scientists in the audience raised doubt about whether the stem cells could have actually been injected into the spinal cord as described, given the large volume reported.
No major adverse events were reported in the first six months of the study. There were minor reports of pain as well as sensory, bladder, bowel and motor problems.

The study authors indicate that at both the 3-month and 6-month intervals after the stem cell injections, there was a slight improvement in muscle strength that was greater in the proximal muscles than in the distal muscles. Small improvement in neck flexor muscle strength was noted as well. There were a number of questions from attending scientists about whether there was adequate evidence that the muscle changes could be attributed to the stem cells and not from other factors such as the trauma of the procedure itself.

The investigators will continue the study and report the 12-month end of study findings in a future report. The authors indicate that the stem cell injection was safe and well tolerated, but they cautioned that further studies should be conducted to understand what role the stem cells may be playing. Many clinicians in the audience voiced concerns about safety of injection into the spinal cord and the feasibility and accuracy of this technique. It was noted that the changes in muscle strength could have been a temporary effect of the trauma of the injection or local tissue damage.

The authors stated that it was not clear why there was a difference in the muscle strength in the proximal muscles versus distal muscles. The potential use of stem cells as future carriers for drugs and other therapies was noted. The possibility that the stem cells are acting as neurotrophic/growth factor agents was discussed. Future trials may include newly diagnosed patients and people with a focal form of ALS.

In summarizing the Symposium's clinical presentations, Ed Byrne, MD, noted that as the field begins to start considering Phase I clinical trials of stem cells, investigators have to assure that the biological basis and scientific rationale for the potential treatment is sound. He urged that stem cells be tested in the ALS animal models to learn more about the actions and effects the stem cells are actually having.

Dr. Byrne commented that while there is very little evidence that stem cells can replace motor neurons, it might be possible that stem cells can have an indirect rescuing impact on the motor nerves by altering the environment around the neurons. He encouraged scientists to increase the research focus on how to stimulate stem cells that exist within each person's body (endogenous) to signal the motor nerves damaged by ALS.
Among the issues to consider before stem cell treatment is ready for ALS clinical trials, Dr. Byrne urged the attendees to address:
• Selection of the location of the body for transplantation and/or stimulation of the patient's own existing stem cells
• Technical approach challenges for injection or transplantation
• Need for clinical protocols
• Timing - earlier in the disease is probably better
• Quantification of results with objective tests
• Immunosuppression to prevent rejection response
• Need for follow-up care and treatment
• Long term follow-up or registry of patients who have received stem cells

Noting that at this time there is little evidence in humans that stem cells provide a benefit in ALS, Dr. Byrne advised that the field should move cautiously.


I hope that this is helpful.

Wise.

[maaghouse]

Wise,
Would you recommend the surgery in China for someone who has ALS? The situation today is she cannot walk or use her legs but has total function of trunk and upperbody. It has been about two years from beginning of symptoms. It is really hard to find any information regarding how well the people who have had the surgery (for ALS) are doing. We've read a few reports of three people who have died from the surgery and one or two people who have gotten worse. My friend is 45 and in good health otherwise. Any advise or information you could provide would be appreciated.
Linda's friend

[Wise Young]

Maaghouse, there is not enough information to say that OEG treatment is effective or not in changing the course of ALS. Although several people have reported subjective improvements in fatigue and strength, not everybody have had similar responses. I don't know the circumstances of the three mortalities but one should bear in mind that many of the 30 or so people who have received the treatment are late-stage ALS and surgery is a risk for people who are not in good health and have significant respiratory compromise. In short, this is not a decision that can be made based on scientific evidence because such evidence is not yet available. Wise.

[umairj]

This email address does not seem to work. It will be nice if someone can post email addresses of all the doctors who are doing this stem cell or OEC transplant in a consolidated form


Originally posted by blu stellina:

Dear Caro,
this is Dr.Mazzini's mail address in Torino:MazziniI@libero.it.
Write and she will give you all informations you need.

[Wise Young]

Dr. Mazzini's email address is mazzini.l@libero.it Wise.

[umairj]

Dr. Young,
Thnx alot
Do you have any contact information and update about the Nanjing stem cell trials.

[Wise Young]

UJ, I have posted all the information that I have on the subject. However, let me expand a little bit on the subject from the viewpoint of the published literature on bone-marrow and umbilical cord blood stem cell therapy of ALS.

• Chen R and Ende N (2000). The potential for the use of mononuclear cells from human umbilical cord blood in the treatment of amyotrophic lateral sclerosis in SOD1 mice. J Med. 31: 21-30. Department of Pathology and Laboratory Medicine, New Jersey School of Medicine, University of Medicine and Dentistry, Newark 07103, USA. The SOD1 mice (transgenic B6SJL-TgN(SOD1-G93A)1GUR) have a mutation of the human transgene (CuZn superoxide dismutase gene SOD1) that has been associated with amyotrophic lateral sclerosis (ALS). In a preliminary study, we demonstrated that a megadose of human umbilical cord blood mononuclear cells given intravenously after 800 cGy of irradiation could substantially increase the life span of SOD1 mice. This report is an attempt to confirm and expand the preliminary findings. By repeating the study and raising the number of human cord blood cells from 33.2-34.0 x 10(6) to 70.2-73.3 x 10(6) there was a further significant increase in the life span of the SOD1 mice. The average life of the controls was 123.5 days while that of mice receiving the larger megadose of cells was 162 days. While all the controls were dead by 130 days, the treated group receiving 70.2-73.3 x 10(6) cells had one animal living up to 187 days and one 210 days. In order to obtain a megadose of cells, pooled blood from different donors was used and did not appear to have a negative effect, but indicated a beneficial effect on survival. The clinical significance of these findings may extend beyond the potential treatment for amyotrophic lateral sclerosis. This study confirms and extends the preliminary study whereby increasing the dose of human umbilical cord blood cells we were able to substantially further increase the survival of SOD1 mice.
• Ende N and Chen R (2002). Parkinson's disease mice and human umbilical cord blood. J Med. 33: 173-80. UMD-New Jersey Medical School, Department of Pathology and Laboratory Medicine, 185 South Orange Avenue, C565, Newark, NJ 07103-2714, USA. In 1995, it was suggested that immature stem cells (Berashis Cells) existing in human cord blood might have an ameliorating effect on such neurological diseases as Alzheimer's, amyotrophic lateral sclerosis and Parkinson's disease. Since these predictions, we have been able to successfully extend the length of life of mice with amyotrophic lateral sclerosis [B6SJL-TgN(SOD1-G93A)IGUR], Huntington's Disease (B6CBA-TgN(H.Dexon1)62Gpb and Alzheimer's mice [Tg(HuAPP695.SWE)2576]. Recently we expanded the studies to include mice with Parkinson's Disease. 32 mice, 6-12 weeks old B6CBACa-AW-J/A-Kcnj6<wv> were obtained from Jackson Laboratory, Bar Harbor, Maine. The mice were divided into 3 groups: (A) 10 untreated control mice, (B) 10 mice treated with 5.6 x 10(6) congenic bone marrow mononuclear cells and (C) 12 mice receiving 100-110 x 10(6) HUCB mononuclear cells intravenously. No immunosuppression was used. When 50% of the controls were dead only 1 of the 10 mice receiving congenic marrow and 2 out of 12 mice that received cord blood mononuclear cells were dead. This preliminary study was terminated when the animal's were 200 days old, at that time one out of 10 controls was alive. Out of 10 mice that received congenic bone marrow, 2 were alive. Out of 12 mice that received megadoses of cord blood mononuclear cells 4 were alive. Survival curve of mice that had congenic marrow had a p value of <.05; the survival curve of mice receiving cord blood mononuclear cells had a p value <.001 [Fig 1) compared to controls. Human umbilical cord blood mononuclear cells significantly delayed the onset of symptoms and death of Parkinson's disease mice. This effect was greater than that produced by congenic bone marrow cells.
• Ende N, Chen R and Mack R (2002). NOD/LtJ type I diabetes in mice and the effect of stem cells (Berashis) derived from human umbilical cord blood. J Med. 33: 181-7. Department of Pathology and Laboratory Medicine, New Jersey Medical School, University of Medicine & Dentistry, 185 South Orange Avenue, Newark, NJ 07103, USA. Previously we have successfully delayed the onset of vasculitis and death in MRL Lpr/Lpr mice that are considered to have an autoimmune disease similar to human lupus erythematosus. Likewise, with the use of megadose human umbilical cord blood mononuclear cells, we were able to delay the onset of symptoms and death in SOD1 mice that carry a transgene for amyotrophic lateral sclerosis, considered by some to be an autoimune disease. A similar approach was utilized with NOD/LtJ type 1 diabetic mice. By administering megadoses of human umbilical cord blood mononuclear cells we were able to ameliorate the disease and improved the life span. This occurred to a greater extent than with bone marrow obtained from congenic mice. No immunosuppression was utilized in this study. This study raises the possibility of utilizing human cord blood mononuclear cells in conjunction with pancreatic islet transplantation.
• Ende N, Weinstein F, Chen R and Ende M (2000). Human umbilical cord blood effect on sod mice (amyotrophic lateral sclerosis). Life Sci. 67: 53-9. Department of Pathology and Laboratory Medicine, UMDNJ-New Jersey Medical School Newark, USA. In previous studies we observed that human umbilical cord blood (HUCB) could have a protective effect on the onset of disease and time of death in MRL Lpr/Lpr mice which have an autoimmune disease that may be considered similar to human lupus. We believed a temporary xenograph may have occurred in these animals with the disease process delayed and the life span markedly increased. When HUCB is stored at 4 degrees C in gas permeable bags, there is a decrease of the cell reaction in mixed lymphocyte cultures. The blood, however, maintains a significant number of cells capable of producing replatable colonies. This study attempted to determine the effect of HUCB on SOD1 mice (transgenic B6SJL-TgN(SOD1-G93A)1GUR), which have a mutation of the human transgene, (CuZn superoxide dismutase gene SOD1) that has been associated with amyotrophic lateral sclerosis. We previously developed evidence that the survival of lethally irradiated mice was related to the number of human mononuclear cells administered. In the present study, we decided to investigate the effect of a relatively large dose of human mononuclear cord blood cells on SOD1 mice subjected to a sublethal dose of irradiation preceded by antikiller sera (rabbit anti-asialo). The SOD1 mice show evidence of paralysis at 4 to 5 months. The average expected lifetime of these mice is reported to be 130 days (Jackson Laboratory). In this experiment, there were 23 mice. Two mice died before the onset of paralysis. The remainder were divided into three groups: group I: control group of 4 untreated mice; group II: an experimental group of 6 mice treated with antikiller sera, 800 cGy irradiation plus 5 x 10(6) congenic bone marrow mononuclear cells; group III: another experimental group of 11 mice treated with antikiller sera, 800 cGy irradiation plus 34.2-35.6 x 10(6) HUCB mononuclear cells, previously stored for 17-20 days at 4 degrees C in gas permeable bags. The results were as follows: the average age at death was: (I) 127 days for the untreated control group, (II) 138 days for the group that received 800 cGy of irradiation and congenic bone marrow (BM) and (III) 148 days for the group that received irradiation and HUCB. (P < 0.001 HUCB vs control, p < 0.01 HUCB vs BM). The longest surviving mouse in each group was 131, 153, and 182 days old respectively. In summary, large doses of HUCB mononuclear cells produced considerable delay in the onset of symptoms and death of SOD1 mice. These preliminary results may not only indicate that amyotrophic lateral sclerosis is an autoimmune disease, but may also indicate a possible treatment for a devastating disease and possibly others.
• Garbuzova-Davis S, Willing AE, Zigova T, Saporta S, Justen EB, Lane JC, Hudson JE, Chen N, Davis CD and Sanberg PR (2003). Intravenous administration of human umbilical cord blood cells in a mouse model of amyotrophic lateral sclerosis: distribution, migration, and differentiation. J Hematother Stem Cell Res. 12: 255-70. Center of Excellence for Aging and Brain Repair and Department of Neurosurgery, University of South Florida, College of Medicine, Tampa, FL 33612, USA. Amyotrophic lateral sclerosis (ALS), a multifactorial disease characterized by diffuse motor neuron degeneration, has proven to be a difficult target for stem cell therapy. The primary aim of this study was to determine the long-term effects of intravenous mononuclear human umbilical cord blood cells on disease progression in a well-defined mouse model of ALS. In addition, we rigorously examined the distribution of transplanted cells inside and outside the central nervous system (CNS), migration of transplanted cells to degenerating areas in the brain and spinal cord, and their immunophenotype. Human umbilical cord blood (hUCB) cells (10(6)) were delivered intravenously into presymptomatic G93A mice. The major findings in our study were that cord blood transfusion into the systemic circulation of G93A mice delayed disease progression at least 2-3 weeks and increased lifespan of diseased mice. In addition, transplanted cells survived 10-12 weeks after infusion while they entered regions of motor neuron degeneration in the brain and spinal cord. There, the cells migrated into the parenchyma of the brain and spinal cord and expressed neural markers [Nestin, III Beta-Tubulin (TuJ1), and glial fibrillary acidic protein (GFAP)]. Infused cord blood cells were also widely distributed in peripheral organs, mainly the spleen. Transplanted cells also were recovered in the peripheral circulation, possibly providing an additional cell supply. Our results indicate that cord blood may have therapeutic potential in this noninvasive cell-based treatment of ALS by providing cell replacement and protection of motor neurons. Replacement of damaged neurons by progeny of cord blood stem cells is probably not the only mechanism by which hUCB exert their effect, since low numbers of cells expressed neural antigens. Most likely, cord blood efficacy is partially due to neuroprotection by modulation of the autoimmune process.
• Mazzini L, Fagioli F, Boccaletti R, Mareschi K, Oliveri G, Olivieri C, Pastore I, Marasso R and Madon E (2003). Stem cell therapy in amyotrophic lateral sclerosis: a methodological approach in humans. Amyotroph Lateral Scler Other Motor Neuron Disord. 4: 158-61. Department of Neurology, University of Torino, Italy. mazzini.l@libero.it. INTRODUCTION: Recently it has been shown in animal models of amyotrophic lateral sclerosis (ALS) that stem cells significantly slow the progression of the disease and prolong survival. We have evaluated the feasibility and safety of a method of intraspinal cord implantation of autologous mesenchymal stem cells (MSCs) in a few well-monitored patients with ALS. METHOD: Bone marrow collection was performed according to the standard procedure by aspiration from the posterior iliac crest. Ex vivo expansion of mesenchymal stem cells was induced according to Pittenger's protocol. The cells were suspended in 2 ml of autologous cerebrospinal fluid and transplanted into the spinal cord by a micrometric pump injector. RESULTS: No patient manifested major adverse events such as respiratory failure or death. Minor adverse events were intercostal pain irradiation (4 patients) which was reversible after a mean period of three days after surgery, and leg sensory dysesthesia (5 patients) which was reversible after a mean period of six weeks after surgery. No modification of the spinal cord volume or other signs of abnormal cell proliferation were observed. CONCLUSIONS: Our results appear to demonstrate that the procedures of ex vivo expansion of autologous mesenchymal stem cells and of transplantation into the spinal cord of humans are safe and well tolerated by ALS patients.

[Caro6]

I want to thank everyone and especially Mr Young for sharing a lot of accurate information here and for always being there with answers. I have the biggest respect for Dr Huang who seems to manage to make time answering to questions on this forum.
This is a comfort and shows a big heart for people. My brother is determined to go on with the operation by Dr Huang, so I hope he can have it as soon as possible. Even if I come from a little country and our family has limited knowledge about the world, the "big" changes in medical science,etc., I will do everything that I possibly can to help my brother.
We know already about several people, two of them we've contacted personnaly, that the Dr Huang-operation provides the only hope we can possibly get to slow down the disease. And this already is a miracle for every ALS-patient.
Even if operation contains always a danger, I'm confident that everything is done to avoid risks and even if nothing is really quite sure right now, I seem to find more trust now and comfort reading all of this information.
I do not feel so alone anymore...

Caro

[Lindox]

Caro,
I wish the very best for your brother, you, and your family.

As long as there are Dr. Wise Young and others like him if possible I hope..those
with paralyzing fears..will never feel alone again. This one man is evidence there are Angels who touch the ground.

Help is on the way.

[umairj]

Hi
A friend of mine asked whether this OEG transplant can benefit his Father's cerebellum degeneration. Doctors have failed to make an exact diagnosis and two possibilities are OPCA and ALS. Since his last EMG is clear there is a chance of OPCA. If you have any info please share
Regards
UJ

[Wise Young]

Caro6, I have been doing a lot of thinking about what possible mechanisms may be accounting for the beneficial effects of olfactory ensheathing glial transplants. Let me start by explaining what I know and then speculate from there.

The mechanisms of ALS (and indeed of most neurodegenerative diseases) are not known. In familial ALS, there is evidence that a gene called SOD1 is involved. This gene codes for superoxide dysmutase (SOD) which is responsible for joining two superoxides (an oxygen free radical) to make hydrogen peroxide, which is in turn broken down by another enzyme called catalase. Because of this discovery, many scientists immediately jumped to the conclusion that an abnormality of SOD production is responsible and that oxidative stress of motoneurons is responsible for amyotrophic lateral sclerosis. However, antioxidants did not prove to be useful for slowing or stopping the progression of ALS in people or mice that have been genetically modified to express the SOD1 gene. Furthermore, only about 10% of people with ALS express the SOD1 gene or variants of the gene known to cause ALS. A number of alternative theories have therefore been proposed.

Mutations of SOD1 or other genes may cause the production of abnormal toxic proteins, e.g. peripherin (http://www.als.ca/_news/4106.aspx). Therefore, some scientists have been trying to identify such proteins and interfere with their production. Alternative antioxidant therapies are being tried including Celebrex (a COX-2 inhibitor). Other potential stress factors for neurons are being assessed, including dextromethorphan (a glutamate receptor blocker), since riluzole (another glutamate receptor blocker) appears to extend life by several months. Some of the research has targetted glial cells that are believed to provide essential sustaining factors for neurons, particularly glial-derived neurotrophic factor (GDNF). Unfortuantely, when they gave the GDNF itself to mice, it did not seem to be enough and therefore they are initiating trials to insert the gene into cells so that more GDNF would be produced. Then there have been various attempts to treat SOD1 mice with cell transplants, including bone marrow cells. These is some data suggesting that cell transplants may secrete factors that protect neurons.

So, in many ways, the transplantation of OEG cells is not as far fetched as some of the treatments that have been tried to date. Olfactory ensheathing glia are cells that are known to express a variety of cell adhesion molecules (such as laminin and L1) and growth factors such as GDNF. Some data suggest that these cells promote neuronal growth and survival. On the other hand, it is difficult to explain the rapid improvement in symptoms in patients who have received OEG transplants. In some of the cases, the cells were transplanted some distance away from the places in the brainstem and spinal cord where motoneuronal degeneration is taking place.

I want to emphasize that it is not yet clear that the OEG cell transplants are producing significant improvement in the patients because most of the reported improvements appear to be subjective. However, if it is causing improvements, it is likely to be activing through some other mechanism besides direct effects of the OEG on the neurons. One possibility is that the OEG transplantation is causing widespread and rapid activation of other cells in the central nervous system. For example, injury is known to activate microglia some distance away and microglia may secrete substances that affect neuronal excitability and survival.

Wise.

[golanbenoni]

Originally posted by Wise Young:

However, antioxidants did not prove to be useful for slowing or stopping the progression of ALS in people or mice that have been genetically modified to express the SOD1 gene.


Dr. can you comment on the latest press release by Aeolus Pharmaceuticals which claims to have developed a catalytic antioxidant which targets oxygen-derived free radicals and what may have made them succesful where others have not:

http://www.aeoluspharma.com/ALS_Crow_experiments.htm

Effect of AEOL 10150 treatment at symptom onset on survival of G93A transgenic ALS mice

Twenty-four confirmed transgenic mice were alternately assigned to control, or AEOL 10150-treatment on the day of symptom onset, which was defined as a noticeable hind-limb weakness. Treatment began on the day of symptom onset. The initial dose of AEOL 10150 was 5 mg/kg interperitoneally (IP), with continued treatment at a dose of 2.5 mg/kg/once a day IP until death or moribundity.


Table 1 and Figure 1 show that AEOL 10150 treatment was associated with an extension of survival after symptom onset, with a mean survival interval of 2.5 times the survival interval of control. AEOL 10150-treated mice were observed to remain mildly disabled until a day or two before death. In contrast, control mice experienced increased disability daily.


Golan.

[Wise Young]

Golan, if confirmed, this is good news indeed. Wise.

[golanbenoni]

Originally posted by Wise Young:

Golan, if confirmed, this is good news indeed. Wise.

Dr. Young,

I spoke for about 15 minutes to the president of AEOLUS Pharma -- They are now conducting limited trials (using single dose only) through participating clinics around the U.S. He says that the trials in animals are promising, but a true test will be what happens in Humans.

We now face a seperate issue, which is -- into which trial should we attempt to enroll my brother in law, Shmuel -- I'm assuming that the folks administering the trials would only want to see their patients enrolled into a single trial -- otherwise, there would be no way to determine efficacy.

Golan.

[Wise Young]

Golan, how long do they want to follow the patients in the trial? I don't think that the issue will be Dr. Huang since I don't think he would mind superimposing OEG transplants on top of another therapy. It is what Aeolus requires. Wise.

[Wise Young]

Here are several abstracts concerning AEOL 10150. Sheng, et al. (2004) treated a mouse compression model of spinal cord injury, using AEOL 10150. This is the antioxidant that we are referring to. They found that neither intravenous AEOL 0.5 mg/kg bolus of the drug followed by 1 mg/kg/hour for 24 hours nor intravenous methylprednisolone iimproved rotarod performance. However, when they gave intrathecal AEOL 10150 (into the spinal fluid), this significantly improved functional recovery and reduced tissue damage. Bowler, et al. (2003) found that AEOL 10150 reduced lung injury associated with hemorrhage (bleeding). In a separate study, Bowler, et al. (2002) reported that AEOL 10150 attenuated inflammatory gene expression in mice after middle cerebral artery occlusion. Sheng, et al. (2002) showed that AEOL 10150 also reduced cell death in culture and a rat middle cerebral artery occlusion model.

The only drug that has been approved by the FDA for the treatment of ALS in humans is riluzole. This drug is a glutamate receptor blocker. However, the effect of this drug is modest, improving survival of patients only by several months. Because the gene associated with ALS is SOD1, a known antioxidant enzyme, much attention has been devoted to antioxidant therapies for ALS but, so far, no positive results have been seen in humans although some positive results have been reported in animal studies. Likewise, there have been many studies of different neurotrophic agents without evidence for efficacy (Dib, 2003). On my next posting, I will try to review all the therapies that are currently in clinical trial.

Wise.

References Cited

Smith, et al., (2002) found that AEOL 10150 reduced the cellular changes in the lung associated with tobacco smoking. Techniques are available to detect this antioxidant in tissues (Kachadourian, et al., 2002). Tse, et al. (2004) showed that catalytic antioxidants suppressed macrophage activation.

So, this antioxidant drug has been found to be potentially neuroprotective in a stroke model and a spinal cord compression model. Antioxidants have long been proposed to be useful for ALS because the gene that is associated with familial ALS has been identified as SOD1 (superoxidase dysmutase) which is an enzyme that breaks down a common oxidant called superoxide. However, many studies treating ALS with antioxidants have failed to show positive results, including vitamin E and other antioxidants. For that reason, a number of researchers have suggested that multiple factors contribute to ALS, including immune responses and changes in the neurons that make them more susceptible to ALS with age. The current theory is that many molecular factors may be activated by toxic factors and that glial cells may contribute to the development of the disease (Bendotti, et al., 2004).








• Bowler RP, Arcaroli J, Abraham E, Patel M, Chang LY and Crapo JD (2003). Evidence for extracellular superoxide dismutase as a mediator of hemorrhage-induced lung injury. Am J Physiol Lung Cell Mol Physiol. 284: L680-7. National Jewish Medical and Research Center, Denver 80206, USA. BowlerR@njc.org. Hemorrhage results in excessive production of superoxide that is associated with severe lung injury. We examined whether the superoxide dismutase (SOD) mimetic manganese(III) mesotetrakis (di-N-ethylimidazole) porphyrin (AEOL 10150) could attenuate this lung injury and whether extracellular (EC)-SOD-deficient mice would have increased hemorrhage-induced lung injury. Compared with wild-type mice, EC-SOD-deficient mice had increased lung neutrophil accumulation, a 3.9-fold increase in myeloperoxidase activity, a 1.5-fold increase in nuclear factor (NF)-kappaB activation, and a 1.5-fold increase in lipid peroxidation 1 h after hemorrhage. Pretreatment with AEOL 10150 did not attenuate neutrophil accumulation but significantly reduced NF-kappaB activation and lipid peroxidation in both wild-type and EC-SOD-deficient mice. The increase in hemorrhage-induced neutrophil accumulation in the lungs of EC-SOD-deficient mice suggests that EC-SOD might play a role in mediating neutrophil recruitment to the lung.
• Bowler RP, Sheng H, Enghild JJ, Pearlstein RD, Warner DS and Crapo JD (2002). A catalytic antioxidant (AEOL 10150) attenuates expression of inflammatory genes in stroke. Free Radic Biol Med. 33: 1141-52. National Jewish Medical and Research Center, Denver, CO 80206, USA. BowlerR@njc.org. Oxidative stress is a major source of injury from cerebral ischemia and reperfusion. We hypothesized that a catalytic antioxidant AEOL 10150 [manganese (III) meso-tetrakis (di-N-ethylimidazole) porphyrin] would attenuate changes in brain gene expression in a mouse model of transient middle cerebral artery occlusion (MCAO). C57BL/6J mice were subjected to either sham surgery or 60 min of right MCAO. AEOL 10150 or phosphate-buffered saline was given intravenously 5 min after onset of reperfusion (n = 6 per group). Six hours later, parenchyma within the MCA distribution was harvested. RNA from the six brains in each group was pooled and mRNA expression determined using an Affymetrix murine MG_U74A v. 2.0 expression microarray. Each experiment was performed three times. The largest changes in expression occurred in stress response and inflammatory genes such as heat shock protein, interleukin-6, and macrophage inflammatory protein-2. Treatment with AEOL 10150 attenuated only the increase in expression of inflammatory genes. This suggests that AEOL 10150 protects brain by attenuating the immune response to ischemia and reperfusion.
• Kachadourian R, Menzeleev R, Agha B, Bocckino SB and Day BJ (2002). High-performance liquid chromatography with spectrophotometric and electrochemical detection of a series of manganese(III) cationic porphyrins. J Chromatogr B Analyt Technol Biomed Life Sci. 767: 61-7. Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA. Recent studies have revealed potent pharmacological activities of manganese-containing cationic porphyrins. An analytical method employing high-performance liquid chromatography with spectrophotometric and electrochemical detection (HPLC-UV/EC) suitable for in vivo applications is described for a series of manganese(III) cationic porphyrins with good separation and resolution. In particular, this method resolved the four atropisomers of manganese(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP5+ or AEOL-10113), verified by mass spectrometry. Electrochemical and spectrophotometric methods of detection were compared using manganese(III) meso-tetrakis(1,3-diethylimidazolium-2-yl)porphyrin (MnTDE-2-ImP5+ or AEOL-10150), the lead catalytic antioxidant of this series. Both methods of detection were quantitative, but electrochemical detection, although less specific for in vivo applications, appears to be considerably more sensitive than spectrophotometric detection.
• Sheng H, Enghild JJ, Bowler R, Patel M, Batinic-Haberle I, Calvi CL, Day BJ, Pearlstein RD, Crapo JD and Warner DS (2002). Effects of metalloporphyrin catalytic antioxidants in experimental brain ischemia. Free Radic Biol Med. 33: 947-61. Department of Anesthesiology, Multidisciplinary Neuroprotection Laboratories, Duke University Medical Center, Durham, NC 27710, USA. Reactive oxygen species play a role in the response of brain to ischemia. The effects of metalloporphyrin catalytic antioxidants (AEOL 10113 and AEOL 10150) were examined after murine middle cerebral artery occlusion (MCAO). Ninety minutes after reperfusion from 90 min MCAO in the rat, AEOL 10113, AEOL 10150, or vehicle were given intracerebroventricularly. AEOL 10113 and AEOL 10150 similarly reduced infarct size (35%) and neurologic deficit. AEOL 10113 caused behavioral side effects at twice the neuroprotective dose while AEOL 10150 required a 15-fold increase from the neuroprotective dose to cause behavioral changes. AEOL 10150, given 6 h after 90 min MCAO, reduced total infarct size by 43% without temperature effects. Brain AEOL 10150 elimination t(1/2) was 10 h. In the mouse, intravenous AEOL 10150 infusion post-MCAO reduced both infarct size (25%) and neurologic deficit. Brain AEOL 10150 uptake, greater in the ischemic hemisphere, was dose- and time-dependent. AEOL 10150 had direct effects on proteomic events and ameliorated changes caused by ischemia. In primary mixed neuronal/glial cultures exposed to 2 h of O(2)/glucose deprivation, AEOL 10150 reduced lactate dehydrogenase release dose-dependently and selectively preserved aconitase activity in concentrations consistent with neuroprotection in vivo. AEOL 10150 is an effective neuroprotective compound offering a wide therapeutic window with a large margin of safety against adverse behavioral side effects.
• Sheng H, Spasojevic I, Warner DS and Batinic-Haberle I (2004). Mouse spinal cord compression injury is ameliorated by intrathecal cationic manganese(III) porphyrin catalytic antioxidant therapy. Neurosci Lett. 366: 220-5. Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA. This study evaluated the effects of the cationic manganese(III) tetrakis(N,N'-diethylimidazolium-2-yl)porphyrin catalytic antioxidant Mn(III)TDE-2-ImP5+ (AEOL 10150) on outcome from spinal cord compression (SCC) in the mouse. C57BL/6J mice were subjected to 60 min thoracic SCC after discontinuation of halothane anesthesia. In Experiment 1, mice were given intravenous Mn(III)TDE-2-ImP5+ (0.5 mg/kg bolus followed by 1 mg kg(-1) h(-1) for 24 h), methylprednisolone (30 mg/kg bolus followed by 5.4 mg kg(-1) h(-1) for 24 h), or vehicle (n = 25 per group). In Experiment 2, mice were given intrathecal Mn(III)TDE-2-ImP5+ (2.5 or 5.0 microg/kg) or vehicle (n = 18 per group). In both experiments, treatment began 5 min post-SCC onset. Rotarod performance was measured on post-SCC days 3, 7, 14, and 21. On post-SCC day 21, the spinal cord was histologically examined and a total damage score was calculated. Neither intravenous Mn(III)TDE-2-ImP5+ nor methylprednisolone altered rotarod performance (accelerated rate P = 0.11, fixed rate P = 0.11) or mean +/- S.D. total damage score (Mn(III)TDE-2-ImP5+ = 21 +/- 9, methylprednisolone = 24 +/- 8, vehicle = 22 +/- 10; P = 0.47; shams = 0). Intrathecal Mn(III)TDE-2-ImP5+ (both 2.5 and 5.0 microg) given at SCC-onset improved rotarod performance (P = 0.05) and total damage score (2.5 microg = 19 +/- 10, P = 0.04; 5.0 microg =19 +/- 8, P = 0.03) versus vehicle (26 +/- 10). These studies demonstrate sustained benefit from manganese(III) porphyrin catalytic antioxidant therapy after SCC. However, efficacy was dependent upon route of administration suggesting that bioavailability is critical in defining efficacy.
• Smith KR, Uyeminami DL, Kodavanti UP, Crapo JD, Chang LY and Pinkerton KE (2002). Inhibition of tobacco smoke-induced lung inflammation by a catalytic antioxidant. Free Radic Biol Med. 33: 1106-14. Center for Health and the Environment, University of California, Davis, CA 95616, USA. krsmith@ucdavis.edu. Cigarette smokers experience airway inflammation and epithelial damage, the mechanisms of which are unknown. One potential cause may be free radicals either in tobacco smoke or produced during persistent inflammation. Inflammation may also be a driving force to cause airway epithelium to undergo changes leading to squamous cell metaplasia. To test whether tobacco smoke-induced inflammation could be reduced by a catalytic antioxidant, manganese(III)meso-tetrakis(N,N'-diethyl-1,3-imidazolium-2-yl) porphyrin (AEOL 10150) was given by intratracheal instillation to rats exposed to filtered air or tobacco smoke. Exposure to tobacco smoke for 2 d or 8 weeks (6 h/d, 3 d/week) significantly increased the number of cells recovered by bronchoalveolar lavage (BAL). AEOL 10150 significantly decreased BAL cell number in tobacco smoke-treated rats. Significant reductions in neutrophils were noted at 2 d and macrophages at 8 weeks. Lymphocytes were significantly reduced by AEOL 10150 at both time points. Squamous cell metaplasia following 8 weeks of tobacco smoke exposure was 12% of the total airway epithelial area in animals exposed to tobacco smoke without AEOL 10150, compared with 2% in animals exposed to tobacco smoke, but treated with AEOL 10150 (p <.05). We conclude that a synthetic catalytic antioxidant decreased the adverse effects of exposure to tobacco smoke.
• Tse HM, Milton MJ and Piganelli JD (2004). Mechanistic analysis of the immunomodulatory effects of a catalytic antioxidant on antigen-presenting cells: implication for their use in targeting oxidation-reduction reactions in innate immunity. Free Radic Biol Med. 36: 233-47. Diabetes Institute, Division of Immunogenetics, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15213-3205, USA. Reactive oxygen species (ROS) have an indispensable role in controlling the growth of pathogens. Recent evidence also suggests that they can function as second messengers and modulators of the immune system. The identification of many redox-sensitive signal transduction pathways that are necessary for initiating the innate proinflammatory immune response suggests that modulation of these oxidation-reduction reactions may provide a means of therapeutic benefit for controlling inflammatory-mediated diseases. In order to test this hypothesis we employed two catalytic antioxidants (AEOL 10113 and 10150) for the determination of the role of oxidation-reduction reactions in innate immune system activation. Catalytic antioxidants prevented the initiation of the innate immune response in LPS-stimulated macrophages as evidenced by the suppression of proinflammatory cytokines (TNF-alpha, IL-1beta) and ROS (NO2- and O2-). The suppression of proinflammatory cytokine and ROS production correlated with the inhibition of NF-kappaB DNA binding, without any effects on the mitogen-activated protein kinase signaling pathway. Catalytic antioxidants prevented NF-kappaB from binding DNA by an oxidation mechanism that was reversible with the addition of DTT. Although the primary use of these agents was to reduce and scavenge ROS, surprisingly, we also observed the ability of these compounds to exhibit oxidoreductase activity and oxidize redox-sensitive transcription factors such as NF-kappaB. Catalytic antioxidants exhibit antioxidant and pro-oxidant activities and our data further demonstrate the importance of redox balance for the initiation of proinflammation. The coupling of the innate with the adaptive immune response is dependent on TNF-alpha, IL-1beta, NO2-, and O2- generation; therefore, agents like catalytic antioxidants that decrease proinflammatory cytokines and ROS may provide protective effects in diseases in which chronic inflammation plays a pathogenic role.

• Bendotti C and Carri MT (2004). Lessons from models of SOD1-linked familial ALS. Trends Mol Med. 10: 393-400. Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milan, Italy. Ten years ago, the linkage between mutations in the gene coding for the antioxidant enzyme Cu,Zn superoxide dismutase (SOD1) and the neurodegenerative disease known as familial amyotrophic lateral sclerosis (FALS) was established. This finding has prompted a myriad of new studies in experimental models aimed at investigating the toxic function of the mutant enzymes. The cellular functions that are impaired in motoneurons as a consequence of molecular alterations induced by the expression of FALS SOD1 converge on pathways that might be activated in sporadic ALS by other toxic factors. Recent data demonstrate that, although motoneurons are lost in patients, other cell types are also affected and actively contribute to the pathogenesis of the disease.

• Dib M (2003). Amyotrophic lateral sclerosis: progress and prospects for treatment. Drugs. 63: 289-310. Laboratoire Aventis, Paris, France. michel.dib@aventis.com. Fifteen years ago, a role for excitotoxic damage in the pathology of amyotrophic lateral sclerosis (ALS) was postulated. This stimulated the development of riluzole, the only available treatment for the disease. Since then, the identification of abnormal forms of superoxide dismutase as the genetic basis of certain familial forms of ALS has provided a huge impetus to the search for new effective treatments for this devastating disease. Transgenic mouse models have been developed expressing these aberrant mutants that develop a form of motor neurone disease the progress of which can be slowed by riluzole. Studies in these mice have provided evidence for a role for excitotoxic, apoptotic and oxidative processes in the development of pathology. The mice can be used for testing molecules targeting these processes as potential therapies, to allow the most promising to be evaluated in humans. Several such agents are currently in clinical trials. Many previous clinical trials in ALS were insufficiently powered to demonstrate any relevant effect on disease progression. This situation has been to some extent remedied in the more recent trials, which have recruited many hundreds of patients. However, with the exception of studies with riluzole, the results of these have been disappointing. In particular, a number of large trials with neurotrophic agents have revealed no evidence for efficacy. Nonetheless, the need for large multinational trials of long duration limits the number that can be carried out and makes important demands on investment. For this reason, surrogate markers that can be used for rapid screening in patients of potential treatments identified in the transgenic mice are urgently needed.

[isabel]

I am a spanish girl, my boyfriend has been recently been diagnosed with als. He is only 28 years old.
Please my english is not very good, but I try to find some treatment for him, I have read something about Dr. Hongyun Huang, could you send me information about how to contact him.
Your reply is very important for me.
Thank you.

My e-mail:
isabelvivancos@hotmail.com

[golanbenoni]

Wise,

Can you please comment on what your current position is on Dr. Huang's OEG procedure?

Thanks,
Golan.

[Wise Young]

Golan, as you know, I don't think that there is any credible evidence that OEG cell transplants are effective for ALS. The risks of surgery are reasonably low but given the short period of time that most people have, I want to warn people that they might be wasting their time. Wise.

[golanbenoni]

Wise Young:
However, many studies treating ALS with antioxidants have failed to show positive results, including vitamin E and other antioxidants.


Wise,

There is new research out this week which seems to indicate that taking vitamin E may actually be harmful. While it has been known for some time that certain vitamins taken in excess can be harmful, I believe this study may come to change what we believe may be in excess.

Vitamin E May Do More Harm Than Good, Study Finds (http://carecure.org/forum/showthread.php?t=2960)

[aspasia]

My father is a 65-year old Greek, living in Greece and has been diagnosed with ALS in January 2000. The only treatment until now is : 3 x 400 NEUPONTIN tablets and 2 5ml tablets of PILUTEK (riluzole), as well as vitamin cocktails. After March 2002 due to respiratory problems he uses a ventilator in order to breath. At this time, he is unable to move any part of his body and he has swallowing problems.
I have read about Dr Hongyun Huang's OEC transplantation and I would be highly appreciate it, if you could inform me about whether and how my father could profit from the treatment, although I do not know if the treatment is appropriate for his condition.
1) Do you recommend OEC transplantation for a patient like my father?
2) Is it necessarily to travel in Chaoyang Hospital of China or it would be possible to do the operation somewhere nearer to Greece?
3) The effect of the operation contains dangers due to the ventilator use?
I would very much appreciate your help or any information you can provide me with.
I hope you understand the urgency of his condition.

[Wise Young]

golan, yes, I heard about the vitamin E and commented on it in a Care Topic (http://carecure.org/forum/showthread.php?t=8413). Note that this refers to high doses of the vitamin. I think that taking normal doses is justified.

aspasia, I am very sorry to hear of your father. To my knowledge, Dr. Huang is the only person in the world that is transplanting fetal olfactory ensheathing glia into patients with ALS. While Doctor Lima in Lisbon (Portugal) is transplanting olfactory mucosa (taken from the same person's nose) into the spinal cord, I don't think that he is transplanting from older people or for ALS. Given your father's condition, the fact that he is on a respirator, travel to China would be very risky and difficult. The evidence for treatment efficacy is also not yet convincing. I don't think that surgery is more dangerous for a person on a respirator. Due to the risks of travel and the still unknown benefits of the treatment, I would not recommend it. However, you should consult with Dr. Huang. He may have a different opinion. Wise.

[trophic]

Originally posted by Wise Young:

Golan, as you know, I don't think that there is any credible evidence that OEG cell transplants are effective for ALS. The risks of surgery are reasonably low but given the short period of time that most people have, I want to warn people that they might be wasting their time. Wise.

It's precisely becaue the period of time available to us is so short that we are willing to undertake what we understand is an experimental procedure that may have no effect or only short-term effects. There is, after all, no alternative other than to do nothing at all.

[Wise Young]

trophic, I understand. Wise.

[golanbenoni]

Originally posted by trophic:

It's precisely becaue the period of time available to us is so short that we are willing to undertake what we understand is an experimental procedure that may have no effect or only short-term effects. There is, after all, no alternative other than to do nothing at all.

Trophic,

I spent an hour on the phone last night with Steven Byer, who you may recall appeared on National Television together with his son, Ben in a program together with Dr. Young to discuss OEG treatment in Beijing. We discussed the current state of the OEG treatments, and he felt very strongly that it has come along way for ALS patients in the last six months alone. This seems to parallel comments I've heard Dr. Young state with regards to improvements of the procedure itself over time (With regards to improvements in the safety of the procedure as well as its effectiveness). It is still not considered a "cure", but it continues to have a modest impact in many patients.

He and his wife have dedicated their time (18 hours a day) to assisting other families with ALS receive OEG treatments, as well as an alternative medicinal treatment known as BNG (under the direction of YongChao Xia and MengQi Xia, M.D., PH.D.)

Steven Byer has made himself available to anyone who wants to contact him with regards to any of the two treatments, and if you are interested, you can email him at: bsbyer@mhtc.net -- He is currently traveling in Beijing to assist patients, but remains in contact.

Although we have not made our decision to send Shmuel to Beijing to receive OEG treatment at this time, we have decided to put him onto the BNG treatment (in attempt to stablize his condition) while we await for other trials to begin here in the States (such as AAV IGF1).

Golan.

[leobutti]

Hi Dr. Wise!

We are so surprise with this comunity!
You are sky angels.

We are from Brasil. My uncle has ALS in early stage.

I want to kwow what do you think about Biomark Cia. They send by $18.000 (euros) a injection of stem cells for ALS tratament.

It's results like chineses Dr. Huang's brain surgery in PALS. The testemunal in site are unbeliveble.

Visit http://www.biomark-intl.com/

I have to do something. I can't stay wacthing my uncle and my family in this condiction.

Or Beijing or Biomark.

What do you thing about?

Help us.

Thanks.

[Wise Young]

Leonardo,

I don't think that the treatment being offered by this Biomark International is based on sound scientific information. Let me first review available evidence for umbilical cord blood effects on spinal cord injury and then on amyotrophic lateral sclerosis.

Spinal cord injury. Although a few studies have reported that CD34+ umbilical cord blood cells transplanted directly into spinal cord may improve recovery in rats after injury (Zhao, et al., 2004; Li, et al., 2004) and one study suggested that intravneous infusion human umbilical cord blood into rats can improve recovery after spinal cord injury (Saporta, et al., 2003), all these studies gave the cells shortly after injury. CD34+ is also a marker of hematopoietic cells (i.e. cells that make blood cells) as opposed to cells that make neurons or glia. To my knowledge, nobody has shown that intraspinally transplanted umbilical cord blood cells replace neurons or stimulate regeneration in chronically injured animal spinal cord. There was one report that Koreans have transplanted well-matched human umbilical cord blood "stem cells" into the spinal cord of a patient at 20 years after injury and apparently improved her walking but, as I have explained before, this is only one case and it is not clear how much she improved and whether the transplant was responsible.

Amyotrophic Lateral Sclerosis. Garbuzova-Davis, et al. (2003) reported that transfusion of G93A SOD1 mice (a mouse that has a gene known to cause ALS) with human umbilical cord blood delayed disease progression by 2-3 weeks and increased survival of the mice. They claim that the cells migrated into the brain and spinal cord of the mice, and expressed neural markers. I have read this study and am not convinced that they have shown that the cells have replaced motoneurons. However, the cells may have protected or slowed down degeneration of the motoneurons. Ende, et al. of New Jersey Medical School in Newark (http://www.geocities.com/CollegePark/Quad/4303/ende.html) had likewise reported that human umbilical cord blood slightly improved survival of SOD1 mice from 127 days to 148 days. Please note, however, that both these experiments gave HUGE doses of human umbilical cord blood to the mice and immunosuppressed them. For example, Ende, et al. irradiated the mice with 800 cGy and then infused 35 million mononuclear human umbilical cord blood. For comparison, I think that the telemark treatment is about 5 million CD34+ cells to a human. A mouse weighs 20-30 grams compared to a 50-60 kg human.

Dr. Mitchell Ghen in Atlanta and Dr. Daniel Cosgrove treated 9 ALS patients in Atlanta (source: ALS TDF (http://www.als.net/treatments/reviews/reviewsarticle.asp?articleid=1634)) with umbilical cord and placental blood cell infusions. Even anecdotal results apparently have been quite mixed. Several patients thought that the treatment had a very positive effect which others thought that it had no effect or may have even made them worse. ALSTDF and ALSA (http://www.rideforlife.com/archives/000350.html) are trying to facilitate a clinical trial of umbilical cord blood treatment to determine whether the treatment is safe and effective.

An Atlantic Journal and Constitution (http://www.alsa-or.org/research/HUCB.htm) story in March 29, 2003 reported that the FDA investigated Dr. Ghen and contacted the Florida blood bank that was supplying him. Dr. Ghen stopped providing the transfusion. Apparently, Dr. Cosgrove also stopped providing the treatment after learning of the FDA investigation. Apparently, the patients paid $25,000 but they received up to 20 units of cord blood (a lot). Please note that a number of unscrupulous physicians have made unwarranted claims for umbilical cord blood therapies of Parkinson's disease and other conditions (see: Cord Blood Research (http://www.parentsguidecordblood.com/research.html))

Wise.

References cited

1. Zhao ZM, Li HJ, Liu HY, Lu SH, Yang RC, Zhang QJ and Han ZC (2004). Intraspinal transplantation of CD34+ human umbilical cord blood cells after spinal cord hemisection injury improves functional recovery in adult rats. Cell Transplant. 13: 113-22. National Research Center for Stem Cell Engineering & Technology, State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, People's Republic of China. The present study was designed to compare the functional outcome of the intraspinal transplantation of CD34+ human umbilical cord blood (CB) cells with that of human bone marrow stromal (BMS) cells in adult rats with spinal cord injury. Sixty adult Wistar rats were subjected to left spinal cord hemisection, and then divided into three groups randomly. The control group received an injection of PBS without cells, while the two other groups of rats received a transplantation of 5 x 10(5) CD34+ CB or BMS cells, respectively. Functional outcome was measured using the modified Tarlov score at days 1, 7, 14, 21, and 28 after transplantation. A statistically significant improvement in functional outcome and survival rate in the experimental groups of rats was observed compared with the control group. Rats that received CD34+ CB cells achieved a better improvement in functional score than those that received BMS cells at days 7 and 14 after transplantation. Histological evaluation revealed that bromodeoxyuridine (BrdU)-labeled CD34+ CB and BMS cells survived and migrated into the injured area. Some of these cells expressed glial fibriliary acidic protein (GFAP) or neuronal nuclear antigen (NeuN). Our data demonstrate for the first time that intraspinal transplantation of human CD34+ CB cells provides benefit in function recovery after spinal cord hemisection in rats and suggest that CD34+ CB cells may be an excellent choice of cells as routine starting material of allogenic and autologous transplantations for the treatment of spinal cord injury.

2. Li HJ, Liu HY, Zhao ZM, Lu SH, Yang RC, Zhu HF, Cai YL, Zhang QJ and Han ZC (2004). [Transplantation of human umbilical cord stem cells improves neurological function recovery after spinal cord injury in rats]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 26: 38-42. State Key Laboratory of Experimental Hematology, Institute of Hematology, CAMS and PUMC, Tianjin 300020, China. OBJECTIVE: To study whether intraspinally transplanted human cord blood CD34+ cells can survive, differentiate, and improve neurological functional recovery after spinal cord injury in rats. METHODS: Rats were randomly divided into two groups. One group of rats was subjected to spinal cord left-hemisection and transplanted with human cord blood CD34+ cells labeled by bromodeoxyuridine (BrdU); The other group was carried by left-hemisection with injection of PBS (control group). The neurological function was determined before and 24 h, 1, 2, 3 and 4 weeks after spinal cord injury and cell transplantation using the modified Tarlov score. The distribution and differentiation of transplanted human cord blood cells in vivo in rat spinal cord were evaluated by histological and immnuhistochemical analysis. RESULTS: Functional recovery determined by modified Tarlov score was significantly improved in the group receiving human cord blood CD34+ cells compared with the control group (P < 0.05). Moreover, human cord blood CD34+ cells were found to survive in rat spinal cord microenvironment, with the expression of the neural nuclear specific protein [NeuN) in 2% BrdU-reactive human cells and of the astrocytic specific protein glial fibrillary acidic protein [GFAP) in 7% BrdU-reactive human cells. CONCLUSIONS: Intraspinally administered human cord blood CD34+ cells can survive, differentiate, and improve functional recovery after spinal cord injury in rats. Transplantation of human cord blood cells may provide a novel strategy for the treatment of neural injury.

3. Garbuzova-Davis S, Willing AE, Zigova T, Saporta S, Justen EB, Lane JC, Hudson JE, Chen N, Davis CD and Sanberg PR (2003). Intravenous administration of human umbilical cord blood cells in a mouse model of amyotrophic lateral sclerosis: distribution, migration, and differentiation. J Hematother Stem Cell Res. 12: 255-70. Center of Excellence for Aging and Brain Repair and Department of Neurosurgery, University of South Florida, College of Medicine, Tampa, FL 33612, USA. Amyotrophic lateral sclerosis (ALS), a multifactorial disease characterized by diffuse motor neuron degeneration, has proven to be a difficult target for stem cell therapy. The primary aim of this study was to determine the long-term effects of intravenous mononuclear human umbilical cord blood cells on disease progression in a well-defined mouse model of ALS. In addition, we rigorously examined the distribution of transplanted cells inside and outside the central nervous system (CNS), migration of transplanted cells to degenerating areas in the brain and spinal cord, and their immunophenotype. Human umbilical cord blood (hUCB) cells (10(6)) were delivered intravenously into presymptomatic G93A mice. The major findings in our study were that cord blood transfusion into the systemic circulation of G93A mice delayed disease progression at least 2-3 weeks and increased lifespan of diseased mice. In addition, transplanted cells survived 10-12 weeks after infusion while they entered regions of motor neuron degeneration in the brain and spinal cord. There, the cells migrated into the parenchyma of the brain and spinal cord and expressed neural markers [Nestin, III Beta-Tubulin (TuJ1), and glial fibrillary acidic protein (GFAP)]. Infused cord blood cells were also widely distributed in peripheral organs, mainly the spleen. Transplanted cells also were recovered in the peripheral circulation, possibly providing an additional cell supply. Our results indicate that cord blood may have therapeutic potential in this noninvasive cell-based treatment of ALS by providing cell replacement and protection of motor neurons. Replacement of damaged neurons by progeny of cord blood stem cells is probably not the only mechanism by which hUCB exert their effect, since low numbers of cells expressed neural antigens. Most likely, cord blood efficacy is partially due to neuroprotection by modulation of the autoimmune process.

4. Ende N, Weinstein F, Chen R and Ende M (2000). Human umbilical cord blood effect on sod mice (amyotrophic lateral sclerosis). Life Sci. 67: 53-9. Department of Pathology and Laboratory Medicine, UMDNJ-New Jersey Medical School Newark, USA. In previous studies we observed that human umbilical cord blood (HUCB) could have a protective effect on the onset of disease and time of death in MRL Lpr/Lpr mice which have an autoimmune disease that may be considered similar to human lupus. We believed a temporary xenograph may have occurred in these animals with the disease process delayed and the life span markedly increased. When HUCB is stored at 4 degrees C in gas permeable bags, there is a decrease of the cell reaction in mixed lymphocyte cultures. The blood, however, maintains a significant number of cells capable of producing replatable colonies. This study attempted to determine the effect of HUCB on SOD1 mice (transgenic B6SJL-TgN(SOD1-G93A)1GUR), which have a mutation of the human transgene, (CuZn superoxide dismutase gene SOD1) that has been associated with amyotrophic lateral sclerosis. We previously developed evidence that the survival of lethally irradiated mice was related to the number of human mononuclear cells administered. In the present study, we decided to investigate the effect of a relatively large dose of human mononuclear cord blood cells on SOD1 mice subjected to a sublethal dose of irradiation preceded by antikiller sera (rabbit anti-asialo). The SOD1 mice show evidence of paralysis at 4 to 5 months. The average expected lifetime of these mice is reported to be 130 days (Jackson Laboratory). In this experiment, there were 23 mice. Two mice died before the onset of paralysis. The remainder were divided into three groups: group I: control group of 4 untreated mice; group II: an experimental group of 6 mice treated with antikiller sera, 800 cGy irradiation plus 5 x 10(6) congenic bone marrow mononuclear cells; group III: another experimental group of 11 mice treated with antikiller sera, 800 cGy irradiation plus 34.2-35.6 x 10(6) HUCB mononuclear cells, previously stored for 17-20 days at 4 degrees C in gas permeable bags. The results were as follows: the average age at death was: (I) 127 days for the untreated control group, (II) 138 days for the group that received 800 cGy of irradiation and congenic bone marrow (BM) and (III) 148 days for the group that received irradiation and HUCB. (P < 0.001 HUCB vs control, p < 0.01 HUCB vs BM). The longest surviving mouse in each group was 131, 153, and 182 days old respectively. In summary, large doses of HUCB mononuclear cells produced considerable delay in the onset of symptoms and death of SOD1 mice. These preliminary results may not only indicate that amyotrophic lateral sclerosis is an autoimmune disease, but may also indicate a possible treatment for a devastating disease and possibly others.

[This message was edited by Wise Young on 01-21-05 at 01:35 AM.]

[sbdspray]

Dr. Young- If ALS kills motor nerves in the brain and spinal cord, couldn't this procedure help someone like me with a SCI to my anterior Lumbosacral grey horns? My SCI has to do with infarction of grey matter, couldn't this apply to SCI as well as ALS?

sherman brayton

[jff23]

bump.

Dr young just wondering what your thoughts were regarding Brayton's question as it applies to grey matter injuries.

thanks

[Wise Young]

Sherman, as far as I can tell, no study has shown that OEG cells replace neurons, particularly motoneurons. I think that the hope is that the cells will slow down the motoneuronal degeneration. Wise.

[JNNY]

When OEG and SCs were co-cultured the number of regenerating neurites was reduced.Consequently, any effective treatment to repair spinal cord injuries using OEG cells normally surround and protect neurons.We further reasoned that motor training would enhance the effects of OEG treatment perhaps by reorganizing the spinal sensorimotor circuits.
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JNNY