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Thread: OEG Treatment of ALS

  1. #21
    Dr. Young,
    Thnx alot
    Do you have any contact information and update about the Nanjing stem cell trials.

  2. #22
    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.

  3. #23
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    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

  4. #24
    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.

  5. #25
    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

  6. #26
    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. 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.

  7. #27
    Senior Member golanbenoni's Avatar
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    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.

  8. #28
    Golan, if confirmed, this is good news indeed. Wise.

  9. #29
    Senior Member golanbenoni's Avatar
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    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.

  10. #30
    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.

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