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Thread: OEG Treatment of ALS

  1. #1

    OEG Treatment of ALS

    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. 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 and a listing of recent publications on ALS and other neurodegenerative disorders can be found in a topic entitled Neurodegeneration Research Forum. 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. Finally, I posted some information about bone marrow transplants in Italy and Nanjing below.

    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)

    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.]
    Last edited by Jeff Weeks; 08-25-2005 at 03:03 PM. Reason: Fixing links

  2. #2
    Member rdco's Avatar
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    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.

  3. #3
    Super Moderator Sue Pendleton's Avatar
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    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.

  4. #4
    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/art...gi?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/depa...edprotocol.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/ste...ppendix_l.html

  5. #5
    Member rdco's Avatar
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    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.

  6. #6
    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.

  7. #7
    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.

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    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

  9. #9
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    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

  10. #10
    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

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