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Thread: A summary of cell-based therapies being tried now in people with spinal cord injury around the world

  1. #1

    A summary of cell-based therapies being tried now in people with spinal cord injury around the world

    This post is in response to Belle's topic entitled: What approach to take? where she asked about therapies going on around the world. I thought that it might be appropriate to summarize the current state of various cell-based therapies that are being tried in humans and combination therapies that some laboratories are reporting to be more effective.

    Let me try to summarize what is known about the various cell-based treatment of chronic spinal cord injury (>1 year after injury):

    1. Olfactory (nasal) mucosa autografts. in 2001, Lu, et al. in Australia reported that nasal mucosa transplantation to injured spinal cords stimulates regeneration in rats after spinal cord injury. Dr. Carlos Lima and his colleagues in Lisbon, Portugal, have transplanted nasal mucosal tissue from the same person into the spinal cord injury site. They excavate part of the spinal cord in order to make room for the transplant. Because the cells come from the same person, there should not be immune rejection of the cells. Several people on these forums who have had the surgery and appear to be recovering some function. Unfortunately, to date, there has not been a publication of the results so that we do not know what proportion of the people recover function, to what extent, and for how long. It is also unclear to me how many people have received this procedure but it is probably over 3 dozen. I have not heard of any case where there has been loss of function or death but the lack of information does not necessarily mean that these have not occurred.

    2. Adult olfactory ensheating cell autografts. Dr. Mckay-Sims and his colleagues in Brisbane, Australia, have managed to grow olfactory ensheathing glia from the nasal mucosa of two patients and transplanted these about 15 million of these cells into their spinal cords. The study is still in its "double-blind" phase and we do not know whether there has been recovery of function or not. In some ways, this is the most desirable of all the options both from a scientific and clinical point of view. The cells were grown from the nasal mucosa and have been identified in culture as olfactory ensheathing glia. Because the cells come from the same person, there should be less risk of immune rejection of the cells.

    3. Fetal olfactory ensheathing glial transplants. In Beijing, Dr. Hongyun Huang is transplanting fetal olfactory ensheathing glia into the spinal cord of people who are 1-32 years after injury. I believe that over 500 people with spinal cord injury and perhaps another 200 people with other conditions (such as ALS and MS) have received these transplants. The cells are injected into the spinal cord above and below the injury site without cutting or removing part of the spinal cord. To my knowledge, there has been three mortalities in the series, all in people more than 3 months after surgery and from unrelated causes. The cells are obtained from aborted fetuses and therefore are not genetically matched to the person receiving it. Although there is some evidence suggesting that fetal tissues are not rejected as adult tissues, it is likely that these transplants will be rejected from the spinal cord at some point, perhaps 3-4 months after transplantation. Reports of earlier results in the first 171 patients that received such transplants indicate an average of 4-8 dermatomes of sensory recovery and 1-2 motor levels of improvement. Animal studies suggest that olfactory ensheathing glia will migrate from the injection site into the injury site and surrounding cord, change the environment of the injury site, and promote regeneration of axons. Unfortunately, only about 10% of the patients who have been transplanted have been systematically followed up beyond their 4-6 week hospitalization. Several members of these forums have received such transplants.

    4. Bone marrow stem cell autografts (adult).
    • Dr. Tarcisio Barros at the University of Sao Paulo in Brazil has transplanted bone marrow mesenchymal stem cells into the spinal cord of about 30 patients with chronic spinal cord injury. Some evidence from animal studies indicate that bone marrow contain stem cells and that these cells can be persuaded to produce neurons in culture. The cells were apparently injected through the vascular system into the blood vessels of the spinal cord. Dr. Barros has reported some initial promising results in terms of somatosensory evoked potential improvement in the patients. It is not clear how much motor improvement the patients are getting. Because the cells are autografts, they are not likely to be rejected.
    • Zhengzhou. Dr. Zhang at the Henan People's Provincial Hospital in Zhengzhou, China told me that he has transplanted bone marrow stem clls to dozens of people with spinal cord injury. The results are not clear but they are looking for ways to improve the results. On my last visit there in January 2005, they have transplanted bone marrow stem cells into over 180 patients with strokes and spinal cord injury. They grow the cells, sort them for those that are CD-43 positive, and then transplant them into the spinal cord.
    • Nanjing. I have heard that there is a group of surgeons in Nanjing (China) that have transplanted bone marrow stem cells into 90 patients with amytrophic lateral sclerosis (ALS). These cells were apparently directly transplanted into the brain and spinal cord.
    • Italy. I have also seen several reports of bone marrow stem cell transplants being used in Italy to treat patients with amyotrophic lateral sclerosis.

    5. Fetal olfactory ensheathing glia and neural stem cell transplants. Dr. Samuiel Rabinovich and his colleagues in Novosibirsk have transplanted a mixture of olfactory ensheathing glia and neural stem cells into the spinal cord of patients with chronic injuries. These cells are apparently cultured from olfactory bulbs obtained from aborted fetuses. They report improvements in motor and sensory function in the patients. These results were published recently. It is not clear what cells were being injected.

    6. Fetal spinal cord transplants. In the United States (Russia and Sweden as well), probably over 200 patients have received various fetal spinal cord transplants into the injury site. The results have been published in a few papers but most of the studies suggest modest recovery of function.

    7. Adult Schwann cell autografts.
    • Yale University. Timothy Volmer transplanted Schwann cells grown from peripheral nerves into two patients with multiple sclerosis. Dr. Volmer has moved to Barrows Neurological Institute in Phoenix, Arizona. A recent email suggested that he has finally re-organized his team and will be starting his clinical trials again. The trial was funded by the Myelin Project.

    8. Fetal Schwann cell transplants. In Kunming (Yunnan) in China, neurosurgeons there have transplanted fetal Schwann cells from aborted fetuses into about 90 patients with chronic spinal cord injury. They are reporting some improvement in function although there is some skepticism by visiting clinicians that these improvements are due to the transplants or to decompressive surgery.

    9. Porcine fetal neural stem cell transplants. At the Washington University in St. Louis and Albany Medical Center, 10 patients have received transplants of neural stem cells obtained from fetal pig brains. This was in a clinical trial sponsored by Diacrin. The cells are apparently grown from pig brain, treated with antibodies to reduce the likelihood of immune rejection, and then transplanted into the spinal cord. The results of this trial have not yet been reported.

    10. Human fetal neural stem cell transplants. I have met several doctors in China (Beijing and Guangzhou) who have grown human fetal neural stem cells from aborted fetuses and transplanted these into the spinal cords of people with acute or chronic spinal cord injury. Apparently, these patients have not gotten much recovery and most of these centers are no longer transplanting these cells.

    11. Adult activated macrophage autografts. The company Proneuron carried out two phase 1 trials in Israel and in Europe in patients that are within 2-3 weeks after spinal cord injury. The cells were obtained from the blood of the patients, cultured and activated on skin, and then transplanted into the spinal cord exposed by laminectomy. This trial has started in the United States at three centers: Craig Hospital in Denver, Kessler Rehabilitation Institute in New Jersey, and Mt. Sinai Hospital in New York.

    12. Adult peripheral nerve autografts.
    • Dr. Carl Kao, a neurosurgeon who operates in Quito, Equador, has transplanted peripheral nerves of about 600 patients over the past 10-15 years. He also places omentum on the spinal cord which apparently is causing epidural cyst formations in some patients. The peripheral nerves should contain Schwann cells.
    • Dr. Henreich Cheng, a neurosurgeon in Taiwan, has used peripheral nerves to bridge transected spinal cords and treated with several growth factors including basic fibroblast growth factor. In 1995, he published a widely recognized paper with Lars Olson, reporting that axons will grow across the transection site and restore function. Since returning to Taiwan, he has apparently carried out this procedure in some patients. He has not yet published the results.

    13. Activated Macrophage Autografts. In 1998, Michal Schwartz reported that activated macrophages improves neurological recovery of rats after spinal cord injury. An Israeli company called Proneuron initiated a phase 1 clinical trial to assess this treatment in patients within 3 weeks after injury. Melissa Holly was the first patient to undergo this therapy about 3 years ago. She showed substantial improvement. Perhaps a quarter of the patients who received the treatment showed improvement. A new phase 2 clinical trial is about read to start.

    14. Omentum transplant. In the 1980's, Dr. Harry Goldsmith began transposing omentum to the spinal cord of animals. The omentum is a part of the vascular tissue that surrounds the stomach and intestines. It's job is too carry blood to and food from the gut. Dr. Goldsmith and colleagues transferred the omentum to many patients over the past two decades. In addition, Dr. Carl Kao does omentum transplant.

    15. Umbilical cord blood transplants. There was a news report from Korea of a woman who recovered motor function after having received an umbilical cord blood stem cell transplant. The cells came from an umbilical cord blood bank, matched with the recipient, and then cultured to select for certain cells. The results have not yet been published. There are persistent news reports that Biomark International, a company that was shut down by the FDA and has now moved to London, has infused umbilical cord blood cells into hundreds of patients, some of whom may have spinal cord injury. There are also reports that of umbilical cord blood cell transplants being done in Mexico.

    In short, hundreds or perhaps even thousands of patients have received cell transplants to the spinal cord and brain. Both mortality and morbidity rates of these transplant surgeries appear to be low. For example, Dr. Huang apparently has had less than 1% mortality in operations to transplant fetal olfactory ensheathing glia into patients with chronic spinal cord injury; all the mortality appear to be several months after surgery and not related to the surgery. Thus, cell transplantation therapies appear to be relatively safe and feasible in spinal cord injury. To my knowledge, however, none of these treatments have produced remarkable improvements in the patients that would warrant the word "cure". There are some reports that people do get modest improvement of function, particularly sensory function. Fetal olfactory ensheating glial transplants, for example, appear to restore 4-8 dermatomes of sensation and 1-2 motor levels, both in thoracic and cervical spinal cord injury.

    Recent animal studies suggest that combining cell transplants with other therapies that stimulate regeneration may be the more efficacious than either the transplants or the growth factors alone. In particular, two studies have been reported (one from Miami and the other from San Diego) that suggest that combination cell transplants (Schwann cells plus db cAMP and rolipram, bone marrow mesenchymal stem cells and cAMP) are better than the cell transplants alone or the cAMP alone. Another potential promising combination therapy is Schwann cell transplants combined with a growth factor called GDNF and chondroitinase are better than the cell transplants or the growth factor/chondroitinase alone. There will be more reports of combination therapies in the coming months. I hope that these reports will impel U.S. groups to initiate clinical trials in the United States rather than force Americans to go overseas for these therapies.

    Wise.

    Glossary
    Autograft. This means cells that obtained from one part of the body of an individual and then transplanted into another part of the body. Auto means "to oneself". Heterograft means cells that are obtained from one person (animal) and transplanted to another person (animal). Xenografts means cells that are obtained from another species, i.e. a pig, and transplanted to human.
    Axon. Axon refers to a single nerve fiber that comes from a neuron. It is part of the neuron. When the axon is injured, the part of the axon that has been separated from the neuron cell body dies.
    Chondroitinase. This is a bacterial enzyme that dissolves a family of proteins called chondroitin-6-sulfate proteoglycans (CSPG). Bacteria secrete this enzyme when they infect tissues. CSPG has been shown to inhibit axonal growth and regeneration. Chondroitinase was recently reported to improve regeneration in animals.
    Ensheathing. This refers to the unusual tendency of cells to ensheath or wrap around other cells. In the case of olfactory ensheathing cells (OEC), they wrap around axons. These cells are sometimes called olfactory ensheating glial (OEG) cells because they often express a marker of glial cells called glial fibrillary acidic protein (GFAP).
    Fetal. This means the cells were obtained from aborted fetuses, usually in the second trimester. Note that fetal stem cells are not the same as embryonic stem cells which are derived from blastocysts, the earliest stage of development during the first two weeks after the egg is fertilized.
    Glia. These are cells in the central nervous system that perform several important functions. There are many kinds of glial cells. The most abundant kind of glial cell is called astrocyte. The first and most important function of astrocytes to separate the central nervous system from other tissues. Astrocyte send processes that completely line blood vessels, link up with each other, and form a tight barrier called the blood-brain-barrier. They keep molecules from the body from entering the brain. Astrocytes also regulate the extracellular environment of central nervous tissues and secrete factors that sustain neurons, including GDNF (see neurotrophin). Other kinds of glial cells include oligodendroglia which are special glial cells that myelinate axons in the central nervous.
    Immune rejection. The immune system in our body recognizes foreign cells, tumors, or infections. Immune cells include lymphocytes and macrophages. The lymphocytes needs to come into contact with the cells and become activated. One activated, they release cytokines and other signals to attract other cells and activate them to produce antibodies or kill the cells. Immune suppression means to take drugs that prevent activation of the immune system.
    Myelin. These are membranes that wrap many times around axons and allow them to conduct signals more rapidly and reliably. Axons that have myelin around them are myelinated. In the central nervous system, axons are myelinated by oligodendroglia (see glia) that typically myelinate as many as 20 axons at a time. Axons in the peripheral nervous system are myelinated by Schwann cells. Olfactory ensheating cells will wrap around axons (ensheath) but will also form myelin. Schwann cells and olfactory ensheathing cells will myelinate only one axon at a time.
    Neural stem cells. These are stem cells from the central nervous system that can make many kinds of cells. In fetal brains, these cells are called radial glial cells and located in the cortex. In neonatal or adult brains, these cells are located at the base of the brain, in a place called subventricular zone (SVZ) but a stream of these cells migrate to the hippocampus (a part of the brain responsible for memory) and to the olfactory bulb. Although neural stem cells are believed to be present in the brainstem and spinal cord, neither their identity or location are known.
    Neurotrophins. These are a family of molecules that stimulate the growth of neurons. The original neurotrophin was a molecule called nerve growth factor (NGF) discovered in the 1960's and it stimulates peripheral axons (as well as sensory axons in the central nervous system). Subsequently, several other neurotrophins were discovered, includ brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Glial derived neurotrophic factor (GDNF) is secreted by glial cells in the central nervous system.
    Olfactory. This refers to the part of your nose and neural structures responsible for the sense of smell. The olfactory mucosa is situated on the roof of your nasal cavity. The olfactory nerve leads from the olfactory mucosa to the olfactory bulb, the part of the brain the receives smell sensations.
    Omentum. This is a vascular structure that surrounds your stomach and intestines. It is responsible for sending blood vessels that supply and carry away food. Because the omentum is an actively growing tissue, it will vascularize (send blood vessels) into tissues. Several doctors have used omentum transplants on the spinal cord.
    Peripheral nerve. These are the nerves that go from your central nervous system to other parts of the body. Peripheral nerves are defined by the presence of Schwann cells. For example, the nerve that goes from the brain to the eye (retina) is a central nerve because it does not have Schwann cells. Likewise, the olfactory nerve is considered a central nerve because it does not contain Schwann cells. However, other cranial nerves such as the nerves that go from the brain to the muscles of the eyes or throat are considered peripheral nerves because they contain Schwann cells. The peripheral nerve contains some Schwann cells and some cells that separate bundles of axons.
    Rolipram and cAMP. Rolipram is a drug that blocks an enzyme called phosphodiesterase 4 (PDE-4). PDE-4 breaks down a molecule called cyclic AMP or cAMP. cAMP is an intramessenger that carries out many functions, including increasing excitability and growth of cells. Recent studies suggest that when cAMP levels are high in growing axons, they will ignore molecules in the tissue that might inhibit axonal growth.
    Schwann cells. These are cells that are responsible for myelinating peripheral nerves. In many ways, they look and behave like olfactory ensheathing glia except that brain cells recognizes them as foreign cells and will tend to form barriers around them. Schwann cells generally do not migrate well when transplanted into the brain.
    Stem cells. These cells are pluripotent, i.e. can produce many different kinds of cells. There are three types of stem cells. One is embryonic stem cells that are obtained from blastocysts (the earliest stage of embryonic development); these cells are not only pluripotent but can continue to produce cells indefinitely in culture. Fetal stem cells are from fetuses, usually from the brain or some other tissues. In adults, two types of stem cells have been extensively studied: neural stem cells and mesenchymal stem cells (usually found in blood or bone marrow). Umbilical cord blood cells are probably mesenchymal stem cells as well.

    [This message was edited by Wise Young on 02-21-05 at 02:22 PM.]

  2. #2
    Senior Member Belle's Avatar
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    Thank you!!!

  3. #3
    Fantastic breakdown Dr. Young. Thank you.

    What we do in life echoes in eternity. Maximus - Gladiator

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    Junior Member Liane's Avatar
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    Dear Dr. Young,
    I read your report about Dr. Huang's surgery during your visit in China in 2002 plus this summary report. I am scheduled to go to China for this surgery and am very interested in all your comments/opinions.
    You mention that the transplanted cells are likely to be rejected at some point - 3-4 months after transplantation. Is there evidence of this? What are the chances of rejection?
    Also I don't understand what "4-8 dermatomes of sensory recovery" mean, as well as 1-2 motor levels of improvement. Is that on the ASIA scale of A to E? I am an A paraplegic.
    I would appreciate hearing from you more about Dr. Huang's procedure.
    Thank you, Liane

  5. #5

    A summary of cell-based therapies being tried now in people with spinal cord injury around the world

    Dr. Young,

    In your summary when speaking about Dr. Huangs procedure you mention the cells will most likely be rejected after 3-4 months. Why does this happen? Does this present a danger to the person? Does this stop regeneration? If so, why do some of the current patients to receive the treatment continue to recover after the 3-4 month mark and in some cases after 10 months?

    Also, I believe you have been involved with Fetal olfactory ensheathing glial transplants in rats correct? If so, what have been the long term affects? How long have you measured/followed...1,2,5,10 years?

    Finally, if you were going to undergo the Fetal olfactory ensheathing glial procedure from Dr. Huang, would you elect to have the steroid included in the procedure? Thanks in advance for your response.

  6. #6
    bwolfbau and Liane,

    There is no definite evidence that fetal olfactory ensheathing glial cells are rejected at 3-4 months after transplantation into chronic spinal cords. I was extrapolating based on animal data.

    We have now transplanted neonatal olfactory ensheathing glial cells into injured spinal cords of many rats at various times after injury. In every case, the cells survive for 3-4 weeks and are immunologically rejected when the animals do not receive cyclosporin immunosuppression. Giving methylprednisolone (an anti-inflammatory and anti-immune steroid) also increases the survival of the cells. We have not yet (and to my knowledge, nobody else has either) transplanted fetal olfactory ensheathing glia into animals. However, we have transplanted fetal radial glial cells into the injured rat spinal cord and find that the animals must immunosuppressed or the cells will be rejected for 3-4 weeks. I am assuming that rat time is 4 times faster than human time and therefore suggested that fetal olfactory ensheathing glia transplanted into chronic injured human spinal cords would survive 3-4 months.

    Please note that it is not necessary for the olfactory ensheathing glial cells to survive long-term to foster regeneration in the spinal cord. The process of immune rejection does not seem to be deleterious to spinal cord function and may even be beneficial because we know that inflammation is involved in immune rejection and inflammation produces factors that may stimulate axonal growth. Unfortunately, Dr. Huang simply has not had the resources of time to study all the patients carefully after they were released from hospital. On the other hand, I don't think that any of the people who have received the olfactory ensheathing glial transplants on this site have experienced a reversal of earlier functional gains at 3-4 months after injury.

    We have studied olfactory ensheathing glial transplants in rats only out to 12-14 weeks after injury. As pointed out above, if we apply a factor of four between rat time and human time, this would be equivalent to a year after transplantation in humans. I simply don't have the funds or resources of maintain rats beyond a year. Furthermore, the natural life span of a rat is on the order of two years. In rats where we have observed rejection of olfactory ensheating glia, we have not see a deterioration or reversal of functional gains at 3-4 weeks.

    Liane, regarding 4-8 dermatomes and 1-2 motor levels of improvement and its relationship to ASIA classification, I am not sure that I understand your question. A dermatome represent the sensory field of a spinal cord segment. A 8 dermatome improvement of sensory function would mean, for example, a descent of the sensory level from C7 to T7 (i.e. C8, T1, T2, T3, T4, T5, T6, T7). In practical terms, this would mean that a person gets back sensation in the hands and chest down to below the nipples (T4). I have seen some patients recover sensation down to T10 (the level of the belly button). A 1-2 level motor improvement would mean, for example, a person who is a C7 (triceps) may recover wrist flexion (C8) and possibly some intrinsic hand muscle (T1). Depending on the level and severity of injury, these changes may or may not be associated with a ASIA classification change. For example, if you are currently a T4 ASIA A, you may get back sensation down to T12 and better truncal and abdomenal muscles but may still remain ASIA A (i.e. be a T12 with no rectal sensation or sphincter contraction). Please note, however, that this improvement is only at 4-6 weeks after transplant and does not refer to recovery beyond this period because the data is simply not available.

    Please ask more questions if you do not understand the above.

    Wise.

  7. #7
    Senior Member Belle's Avatar
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    Now *I* have some questions ...

    Is the sensation of each dermatome skin sensation only, or would that include sensations like fullness of stomach or bladder for example?

    What about autonomic system functions - the oddball stuff like blood pressure regulation and hormonal changes - how might the level improvements to dermatome or motor recovery suggest improvements in these functions? BTW - is there a link someone could suggest that details spinal cord sensory, autonomic, and motor functions by level? Technical is OK - I've had an anatomy class and my sister is a doctor.

    I've had pet rats before - maybe you could farm them out to reduce costs, lol. I've worked lab animal care before. I know it doesn't work that way, but geez it would sure feel more helpful than sending off $$$ that just seem to disappear! OTOH, how on earth do you straight cath a rat??? lol!

    If I had known my husband was going to get injured like this, I would have gone for a PhD in something more medically oriented than landscape architecture, sigh...

  8. #8

    A summary of cell-based therapies being tried now in people with spinal cord injury around the world

    Dr. Young,

    Thanks for the quick response. I leave for Beijing on Thursday 7/22 so your comments and analysis have been helpful both now and in the past to make my decision based on as much accurate information as possible. Patricia has also been a big help as I have spoke with her on the phone sevaral times. I promised her that I would keep her updated on my progress over the next several weeks by her email address. I will also keep the carecure members in the loop through this site as much as possible.

    A few more questions...I am strongly considering asking Dr. Huang to use methylprednisolone along with the fetal olfactory ensheathing glial cells. Do you agree with this decision? Is there any other enhancement/different measures you would recommend I discuss with Dr. Huang prior to the procedure? Are you comfortable with 500K cells above and below the site or would you consider more or less? These are probably difficult questions to answer w/o knowing my situation. I am 2 years post C6/C7 and just had a full functional evaluation by Dr. Hinderer at the Detroit Medical Center. The results show me as strong ASIA D, ambulation with the aid of a single cane.

    Any thoughts in addition to what you have already provided, answers to my questions and overall advise as I embark on my journey next week? Thanks again.

  9. #9
    Junior Member Liane's Avatar
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    Dr Young,
    Thank you so much for such a clear response to my questions.

    bwolfbau,
    I would be very much interested in hearing about your experience in Beijing. I am not scheduled to go for a few more months and would appreciate any advice you can give regarding travel, what to take, etc. Good luck with your surgery.

  10. #10
    Dr Young, thanks a lot, this was very Educational and clarifies everything a lot.

    Berny.

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