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This month we have a different type of column for you.
Mr. Thomas Ichim, the CEO of Medistem has written a "state of the science" style column about stem cell therapy as it stands today.
Thomas Ichim is the CEO of Medistem Inc, Chairman of the Scientific Advisory Board of Orcrist Bio, and a Managing Partner of the Vendevia Group. Thomas has served a variety of oversight roles for companies operating in the area of biologics. He obtained numerous regulatory approvals for companies such as MarrowTech Pharma, and worked as a Program Director for the global CRO bioRASI (which he is a co-founder of), under which he led efforts to develop, clinically assess, and approve various stem cell and cellular therapies.
Ichim has also founded two companies, ToleroTech Inc. and MedVax Pharma Corp., which are developing proprietary technologies in the areas of RNA interference and cancer vaccines, respectively. As Managing Partner of Vendevia Group, he plays a pivotal role in new start-up formation, most recently in the establishment and financing of OncoMune, an epigenetic cancer therapy company. Ichim was an invitee to a recent government-sponsored California-Canada trade mission and has been instrumental in establishing Medistem's extensive collaborative network.
In addition to corporate responsibilities, Ichim is an accomplished scientist with numerous publications (>34 on pubmed), including his participation in the award-winning publication on the discovery of the ERC cells, the basis for Medistem's core products.
Ichim has created numerous videos discussing the state of stem cell clinical translation which can be seen at http://www.youtube.com/user/cellmedicine.
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The text of Mr. Ichim's column will be posted below. A PDF file has been attached as well.
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I just had a telephone conversation with the brother of a spinal cord injury patient who was treated with stem cells in China. The brother, lets call him ?Matt? was a friend of a childhood friend of mine, so I could afford a certain degree of informality.
?Do stem cells actually become new nerve cells? How do the stem cells know how to communicate with the damaged cells? If stem cells really work, then why are they not approved in the US?? All of these are very potent questions. So when Barbara asked me to write a column on stem cell therapy, I figured it would only be proper to continue the conversation I had with Matt on a more elaborate basis for the audience of Stem Cell Pioneers. Since I am used to writing publications for medical journals, my experience in ?lay writing? is pretty minimal, therefore I ask you to be patient and if some of the points are not clear, please email your questions and I will be glad to answer them as best I can.
Tom what exactly are stem cells? How are they related to bone marrow transplants?
The field of ?stem cells? was born out of the work of Till and McCulloch who in the 1960s demonstrated one type of cell from the bone marrow could give rise to all of the cells of the blood system. This ability of the cell to make copies of itself, as well as to become different cell types, gained the name ?stem cell?. These stem cells, called ?hematopoietic stem cells?, are commonly used for treatment of cancer patients as part of ?bone marrow transplant? in which high doses of chemotherapy and/or radiation are given to patients, and the patient?s blood system is saved by administration of the donor stem cells. Since the first toxicity of healthy tissue is the blood making system, the ability to give higher levels of cytotoxic therapy allows for cures in some leukemias through transplantation of healthy stem cells. In addition to containing the cells that make blood, the bone marrow contains cells called ?stromal cells? that support the hematopoietic stem cells. Essentially, stromal cells are comprised of various actual cell populations The stroma includes adipocytes, osteoblasts, and mesenchymal stem cells (1). The primary function of mesenchymal stem cells in the bone marrow is to control proliferation of the hematopoietic stem cell, through provided growth factor support. This is why certain scientists are using mesenchymal stem cells to accelerate blood formation after administration of hematopoietic stem cells in patients (2).
So you are saying that there are two main types of adult stem cells, hematopoietic and mesenchymals? Right? Now what do they have to do with curing diseases, you only mentioned about the blood making system of the body.
Exactly. All of this ?stem cell? business started when scientists started studying the bone marrow and the incredible amount of new cells being made there. The next step of the stem cell revolution was when scientists started finding out that various cells from the bone marrow are capable of turning into, or ?differentiating? into other cells of the body. In the early scientific experiments, scientists didn?t distinguish between the bone marrow derived hematopoietic stem cells and mesenchymal stem cells, they simply took whole bone marrow and started injecting it into patients with various diseases (of course after they demonstrated activity in animal models). For example, in 2001 Strauer et al from Germany reported a case in which a 46 year old patient received his own (called ?autologous?) bone marrow cells by a catheter in the artery that was feeding the infracted area. 10 weeks after administration, the area damaged by the heart attack was reduced in size from 24.6 % to 15.7 % of left ventricular circumference. There was also a documented improvement in ejection fraction, cardiac index and stroke volume by 20-30 % (3). Placebo? Maybe, it was after all just one patient ! A subsequent paper in the same year reported administration of bone marrow cells in 5 patients with advanced heart failure undergoing coronary artery bypass grafting. The cells were administered intramuscularly into areas deemed ungraftable and perfusion was assessed by imaging. Specific improvement in areas injected was documented in 3 of the 5 patients. Perhaps more importantly, no growths of abnormal tissues or adverse effects were reported at 1 year follow-up (4). These two studies were important because they gave the suggestion that bone marrow stem cells may have a specific regenerative effect in tissues other than blood forming tissues.
OK, so in 2001 the ?great leap? was made from bone marrow making only blood, to bone marrow being able to fix up other tissues. But still this is only in a total of 6 patients. Means nothing.
Absolutely. But it did show one important point which was that in these situations the bone marrow cells do not become other tissues. For example, since bone marrow has stem cells and stem cells theoretically can become a wide variety of tissues, what if the stem cells became bone tissue? Or even non-functional muscle tissue in the heart?
Now let me address your point about significance. These pioneering studies in 2001 provided the ?comfort level? to investigators internationally to embark on numerous clinical trials using bone marrow stem cells for heart disease. I don?t want to go into details of every clinical trial performed with bone marrow stem cells, so let?s review some of the publications that summarize many of the clinical trials conducted.
The results of 999 patients treated in 18 independent controlled cardiac trials in which patients were treated with either unseparated bone marrow cells, bone marrow mesenchymal, or mobilized peripheral blood stem cells were reviewed by Abdel-Latif et (5). They found that overall in comparison to controls, there was a statistically significant improvement in ejection fraction, reduction in infarct size and left ventricular end-systolic volume. In another meta-analysis Martin-Rendon et al reviewed bone marrow therapy for post acute infarction trials. Of 13 randomized studies examined, encompassing 811 participants, the authors stated that more trials are needed to establish efficacy in terms of clinical endpoints such as death. However a consistent improvement in the heart?s pumping activity, as determined by LVEF, as well as trends for decrease in left ventricular end systolic and end diastolic volumes, and infarct size were noted (6). Two other major overviews of randomized trials in the area of bone marrow stem cell infusions also supported the conclusion of safety and mild but statistically significant improvement in LVEF (7, 8). These data suggest that stem cell therapy, both hematopoietic and mesenchymal have clinical effects in various types of heart failure. Theoretically the leap between these clinical trials and widespread implementation is more of a business question than a medical question.
So before I ask you about other diseases?let me first pose the question?if bone marrow stem cells actually have this therapeutic effect, why do we have to go to Mexico and China to get these treatments commercially? Why cant we just get them in North America?
For full-blown approval of therapeutics, the regulatory agency, whether it is the EMEA in Europe, or the FDA in the US, must review results of at least 2 Phase III double blind trials, and there must be a ?Sponsor? that promotes the therapy and offers it. Unfortunately, when there is little commercial incentive, this is difficult, if not impossible to do.
Can the FDA Accelerate Approval of Stem Cell Therapies?
Stem cell therapy offers hope in conditions which hope was previously unimaginable, however stem cell therapy is a brand new area. Remember, Marie Curie who discovered radioactivity died of leukemia (back then they didn?t know that radioactivity was so carcinogenic). Therefore while there is enormous potential in stem cell therapy, and thousands of people have been treated with stem cells without adverse events, this is a new area of exploration, which with big potential also may have substantial risks. The thalidomide tragedy was avoided in the US because of rigorous examination of the preclinical data.
So you mean that no money can be made from patients using their own bone marrow stem cells and that?s why they are not available commercially?
Well the problem is a bit more complicated. Firstly money can be made. Instead of using unpurified bone marrow, certain companies have figured out that the efficacy of bone marrow stem cells can be increased, at least theoretically, by purifying and concentrating the active ingredients in the bone marrow. For example, Baxter has developed a kit called ?Isolex? that purifies bone marrow CD34 positive stem cells. In March of 2006 Baxter began a Phase II clinical trial
Hold on?I keep hearing these words ?Phase I, Phase II, Phase III?, what does that mean?
The terminology originated in drug development and was adopted by celltherapists. Phase I is when the experimental agent is used in a dose escalating manner to identify the best dose.
How can you increase doses of cells without knowing what they are going to do? When do you stop increasing the dose?
Before Phase I, studies in animals are conducted, called ?preclinical studies? that give some level of approximation as to what doses would be safe in humans, and also what doses should be maximal. Maximal dose is either predetermined, or determined by a certain number of adverse events in the patients studied.
OK so Phase I determines dose, whats Phase II and III?
Phase II looks for efficacy with the dose selected from Phase I. Phase III is confirmation of efficacy, almost always in a double blind (neither doctor nor patient know what is being administered) manner and conducted in multiple centers.
Please continue about Baxter
Yes Baxter started a Phase II trial with their device in patients with chronic heart failure, but actually instead of drilling holes in the bone marrow to extract the stem cells, they give patients a drug that makes the stem cells leave the bone marrow and enter circulation, subsequently the stem cells are shipped to Baxter where the CD34 positive cells are purified and returned to the point of care for infusion into the patient
http://www.baxter.com/about_baxter/news_room/news_releases/2006/03-07-06-stem_cell_trial.html
Ok, so if this works with their system then they can charge money because that is something actually patentable?
Exactly. There is another form of stem cell therapy that is being commercialized. The problem with using your own stem cells comes from the fact that older stem cells do not work as well as younger stem cells, and also that patients that have cardiac risk factors usually have stem cells that work poorly. Therefore, some companies are developing stem cells that are ?universal donor? in other words, they do not need to come from the same individual that is receiving them.
One example of such ?universal donor? stem cells is the bone marrow derived mesenchymal stem cell. The mesenchymal stem cell looks different than the bone marrow blood forming (hematopoietic) stem cell. Specifically, mesenchymal stem cells attach to plastic and have an elongated shape, whereas hematopoietic stem cells are round and float when cultured. Another important difference is that mesenchymal stem cells do not make blood cells, instead, one of their primary functions in the bone marrow is to support the cells that make the blood cells.
If mesenchymal stem cells only support the cells that make blood cells, then why do we call them ?stem cells??
You are correct. Initially scientists believed that only the cells that make the blood cells are stem cells, however further investigations in the 1970s revealed that the ?sticky cells? could become bone and cartilage when treated with special chemicals. The stunning work of Arnold Caplan, whose patents went on to form the company Osiris, demonstrated that mesenchymal stem cells could become muscle and adipose tissue. Further work revealed that under certain conditions mesenchymal stem cells could even become neurons.
So what are mesenchymal stem cells useful for?
Well before I tell you that, I should state that since mesenchymal stem cells protect the blood forming stem cells, and since the blood forming stem cells are sensitive to even minute amounts of inflammation, the mesenchymal stem cells are potently anti-inflammatory. It is believed that this property, in part, is responsible for the ability of mesenchymal stem cells to be transplanted from one human to another without causing rejection.
Given that mesenchymal stem cells make bone and cartilage, these cells were used substantially for healing of injuries to these tissue. Mesenchymal stem cells from the fat, for example, have been used successfully in treating cartilage injuries in more than 1000 racehorses by the company Vet-Stem. Other studies in humans have demonstrated potent therapeutic effects of mesenchymal stem cells in conditions such as graft versus host (GVHD) (9-14), osteogenesis imperfecta (15), Hurler syndrome and metachromatic leukodystrophy (16). The company Osiris has successfully completed Phase I safety studies using mesenchymal stem cells and current conducting efficacy finding clinical trials (Phase II and Phase III) for Type I Diabetes, Crohn?s Disease, and Graft Versus Host Disease using allogeneic bone marrow derived MSC. Intravenous administration of allogeneic MSCs by Osiris was also reported to induce a statistically significant improvement in cardiac function in a double-blind study (17).
Other companies have entered clinical trials using mesenchymal stem cells, and cells similar to mesenchymal stem cells in the US. For example, the company Athersys is currently in Phase I trials using its MultiStem technology, which involves ex vivo expanded MAPC for post-infarct heart repair (18). Angioblast Systems has recently announced initiation of Phase II trials using Mesenchymal Precursor Cells for stimulation of cardiac angiogenesis (19). Neuronyx is in Phase I clinical trials using allogeneic human adult bone marrow-derived somatic cells (hABM-SC) for post infarct healing (20).
Second to bone marrow, another source of mesenchymal stem cells has been the adipose tissue. The company Cytori is currently conducting two European clinical trials using autologous adipose-derived mononuclear cells, of which MSC are believed to be the therapeutic population (21). The PRECISE trial is a 36-patient safety and feasibility study in Europe evaluating adipose-derived stem and regenerative cells as a treatment for chronic cardiac ischemia. The APOLLO trial is a 48-patient safety and feasibility study in Europe to evaluate adipose-derived regenerative cells as a treatment for heart attacks (22). Allogeneic uses of adipose derived MSC included treatment of graft versus host disease associated liver failure (23), and steroid refractory graft versus host disease (24, 25).
But I thought only embryonic stem cells could become different tissues and regenerate the body?
I don?t know?.there are a lot of arguments?but here are some examples of bone marrow cells becoming different tissues?
Tissue Generated
Conditions Used
Institution
Reference
Neurons
Coculture of bone marrow with Swann Cells
Neuroscience Research Unit of the Mapfre Foundation, Madrid, Spain
(26)
Neurons
Neural induction media and Il-1
University of Medicine and Dentistry of New Jersey
(27)
Neurons
Sodium Ferulate
Jiangxi Medical College, Nanchang, China.
(28)
Neurons
Astrocyte conditioned media
University of Cagliari, Italy
(29)
Neurons
alpha-secretase-cleaved fragment of the amyloid precursor protein (sAPPalpha)
Mailman Research Center, McLean Hospital, 115 Mill Street, Belmont, MA USA
(30)
Neurons
NGF
Tel Aviv University,
(31)
Insulin Producing Cells
Nicotinamide containing cocktail
Nanjing Medical University
(32)
Insulin Producing Cells
Islet conditioned media
Centre Hospitalier Universitaire, Grenoble, France
(33)
Insulin Producing Cells
Histone deacetylase inhibitors
German Research Center for Biotechnology, Braunschweig, Germany
(34)
Liver
Fibroblast growth factors
Tottori University, Tottori, Japan.
(35)
Colonic Mucosa
In vivo injury
Osaka University Graduate School of Medicine
(36)
Salivary Glands
Co-culture with rat acinar cells
Graduate Institute of Clinical Dentistry, School of Dentistry, Taipei, Taiwan
(37)
So Tom, how do you fit into all of this?
Being CEO of Medistem, we work on a new type of stem cell deri@
?<Eometrium called the ?Endometrial Regenerative Cell? (ERC). These cells possess a very high activity to secrete growth factors. We use these cells in animal models because we are working at establishing enough data to file with the FDA.
What is Cellmedicine?
The Institute of Cellular Medicine (www.cellmedicine.com) is a clinical that licensed some of the technologies and know-how developed by Medistem. They treat patients with a variety of autologous adult stem cell based therapies.
Why would people go and get stem cell therapy at places like Cellmedicine when it is available in the US as part of clinical trials?
Many patients do not meet the inclusion/exclusion criteria to enter clinical trials. If you are interested, go to www.clinicaltrials.gov and search for ?stem cells?, you will see numerous ongoing trials here in the US. Other patients do not want to risk being the placebo control group.
So does stem cell therapy work?
Depends on the disease and the types of cells used. It is impossible to draw conclusions when 500 patients were treated but all the patients have different diseases and different stages of diseases. Randomized clinical trials are needed that are placebo controlled. These are currently ongoing or there are preparations for their initiation. The problem is that many patients do not want to wait until results come out to know for sure if the specific stem cell therapy works or doesn?t work.
Additionally, places like Cellmedicine (www.cellmedicine.com ) have a certain ability to offer individualized patient therapy based on the conditions and previous history of the patient. While this is good for the patient, it is not good for comparing patients side by side since everything is different.
1. Krebsbach, P.H., Kuznetsov, S.A., Bianco, P., and Robey, P.G. 1999. Bone marrow stromal cells: characterization and clinical application. Crit Rev Oral Biol Med 10:165-181.
2. Koc, O.N., Gerson, S.L., Cooper, B.W., Dyhouse, S.M., Haynesworth, S.E., Caplan, A.I., and Lazarus, H.M. 2000. Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol 18:307-316.
3. Strauer, B.E., Brehm, M., Zeus, T., Gattermann, N., Hernandez, A., Sorg, R.V., Kogler, G., and Wernet, P. 2001. [Intracoronary, human autologous stem cell transplantation for myocardial regeneration following myocardial infarction]. Dtsch Med Wochenschr 126:932-938.
4. Hamano, K., Nishida, M., Hirata, K., Mikamo, A., Li, T.S., Harada, M., Miura, T., Matsuzaki, M., and Esato, K. 2001. Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart disease: clinical trial and preliminary results. Jpn Circ J 65:845-847.
5. Abdel-Latif, A., Bolli, R., Tleyjeh, I.M., Montori, V.M., Perin, E.C., Hornung, C.A., Zuba-Surma, E.K., Al-Mallah, M., and Dawn, B. 2007. Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med 167:989-997.
6. Martin-Rendon, E., Brunskill, S., Doree, C., Hyde, C., Watt, S., Mathur, A., and Stanworth, S. 2008. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev:CD006536.
7. Kang, S., Yang, Y.J., Li, C.J., and Gao, R.L. 2008. Effects of intracoronary autologous bone marrow cells on left ventricular function in acute myocardial infarction: a systematic review and meta-analysis for randomized controlled trials. Coron Artery Dis 19:327-335.
8. Zhang, S.N., Sun, A.J., Ge, J.B., Yao, K., Huang, Z.Y., Wang, K.Q., and Zou, Y.Z. 2008. Intracoronary autologous bone marrow stem cells transfer for patients with acute myocardial infarction: A meta-analysis of randomised controlled trials. Int J Cardiol.
9. Le Blanc, K., Frassoni, F., Ball, L., Locatelli, F., Roelofs, H., Lewis, I., Lanino, E., Sundberg, B., Bernardo, M.E., Remberger, M., et al. 2008. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371:1579-1586.
10. Ning, H., Yang, F., Jiang, M., Hu, L., Feng, K., Zhang, J., Yu, Z., Li, B., Xu, C., Li, Y., et al. 2008. The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients: outcome of a pilot clinical study. Leukemia 22:593-599.
11. Ball, L., Bredius, R., Lankester, A., Schweizer, J., van den Heuvel-Eibrink, M., Escher, H., Fibbe, W., and Egeler, M. 2008. Third party mesenchymal stromal cell infusions fail to induce tissue repair despite successful control of severe grade IV acute graft-versus-host disease in a child with juvenile myelo-monocytic leukemia. Leukemia 22:1256-1257.
12. Ringden, O., Uzunel, M., Rasmusson, I., Remberger, M., Sundberg, B., Lonnies, H., Marschall, H.U., Dlugosz, A., Szakos, A., Hassan, Z., et al. 2006. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 81:1390-1397.
13. Le Blanc, K., Rasmusson, I., Sundberg, B., Gotherstrom, C., Hassan, M., Uzunel, M., and Ringden, O. 2004. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363:1439-1441.
14. Muller, I., Kordowich, S., Holzwarth, C., Isensee, G., Lang, P., Neunhoeffer, F., Dominici, M., Greil, J., and Handgretinger, R. 2008. Application of multipotent mesenchymal stromal cells in pediatric patients following allogeneic stem cell transplantation. Blood Cells Mol Dis 40:25-32.
15. Horwitz, E.M., Gordon, P.L., Koo, W.K., Marx, J.C., Neel, M.D., McNall, R.Y., Muul, L., and Hofmann, T. 2002. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc Natl Acad Sci U S A 99:8932-8937.
16. Koc, O.N., Day, J., Nieder, M., Gerson, S.L., Lazarus, H.M., and Krivit, W. 2002. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant 30:215-222.
17. http://www.osiristx.com/pdf/PR%2039%2025Mar07%20Provacel%20Positive%20Results.pdf.
18. http://ir.athersys.com/releasedetail.cfm?ReleaseID=276046.
19. http://www.angioblast.com/news/pressrelease10.pdf.
20. http://www.neuronyx.com/therapeutic_targets.php.
21. Meliga, E., Strem, B.M., Duckers, H.J., and Serruys, P.W. 2007. Adipose-derived cells. Cell Transplant 16:963-970.
22. http://www.cytoritx.com/intl/products/cv_clinical_trials.html.
23. Fang, B., Song, Y., Zhao, R.C., Han, Q., and Lin, Q. 2007. Using human adipose tissue-derived mesenchymal stem cells as salvage therapy for hepatic graft-versus-host disease resembling acute hepatitis. Transplant Proc 39:1710-1713.
24. Fang, B., Song, Y., Liao, L., Zhang, Y., and Zhao, R.C. 2007. Favorable response to human adipose tissue-derived mesenchymal stem cells in steroid-refractory acute graft-versus-host disease. Transplant Proc 39:3358-3362.
25. Fang, B., Song, Y., Lin, Q., Zhang, Y., Cao, Y., Zhao, R.C., and Ma, Y. 2007. Human adipose tissue-derived mesenchymal stromal cells as salvage therapy for treatment of severe refractory acute graft-vs.-host disease in two children. Pediatr Transplant 11:814-817.
26. Zurita, M., Vaquero, J., Oya, S., Bonilla, C., and Aguayo, C. 2007. Neurotrophic Schwann-cell factors induce neural differentiation of bone marrow stromal cells. Neuroreport 18:1713-1717.
27. Greco, S.J., and Rameshwar, P. 2007. Enhancing effect of IL-1alpha on neurogenesis from adult human mesenchymal stem cells: implication for inflammatory mediators in regenerative medicine. J Immunol 179:3342-3350.
28. Wang, Y., Deng, Z., Lai, X., and Tu, W. 2005. Differentiation of human bone marrow stromal cells into neural-like cells induced by sodium ferulate in vitro. Cell Mol Immunol 2:225-229.
29. Reali, C., Scintu, F., Pillai, R., Cabras, S., Argiolu, F., Ristaldi, M.S., Sanna, M.A., Badiali, M., and Sogos, V. 2006. Differentiation of human adult CD34+ stem cells into cells with a neural phenotype: role of astrocytes. Exp Neurol 197:399-406.
30. Chen, C.W., Boiteau, R.M., Lai, W.F., Barger, S.W., and Cataldo, A.M. 2006. sAPPalpha enhances the transdifferentiation of adult bone marrow progenitor cells to neuronal phenotypes. Curr Alzheimer Res 3:63-70.
31. Kan, I., Ben-Zur, T., Barhum, Y., Levy, Y.S., Burstein, A., Charlow, T., Bulvik, S., Melamed, E., and Offen, D. 2007. Dopaminergic differentiation of human mesenchymal stem cells--utilization of bioassay for tyrosine hydroxylase expression. Neurosci Lett 419:28-33.
32. Wu, X.H., Liu, C.P., Xu, K.F., Mao, X.D., Zhu, J., Jiang, J.J., Cui, D., Zhang, M., Xu, Y., and Liu, C. 2007. Reversal of hyperglycemia in diabetic rats by portal vein transplantation of islet-like cells generated from bone marrow mesenchymal stem cells. World J Gastroenterol 13:3342-3349.
33. Moriscot, C., de Fraipont, F., Richard, M.J., Marchand, M., Savatier, P., Bosco, D., Favrot, M., and Benhamou, P.Y. 2005. Human bone marrow mesenchymal stem cells can express insulin and key transcription factors of the endocrine pancreas developmental pathway upon genetic and/or microenvironmental manipulation in vitro. Stem Cells 23:594-603.
34. Tayaramma, T., Ma, B., Rohde, M., and Mayer, H. 2006. Chromatin-remodeling factors allow differentiation of bone marrow cells into insulin-producing cells. Stem Cells 24:2858-2867.
35. Shimomura, T., Yoshida, Y., Sakabe, T., Ishii, K., Gonda, K., Murai, R., Takubo, K., Tsuchiya, H., Hoshikawa, Y., Kurimasa, A., et al. 2007. Hepatic differentiation of human bone marrow-derived UE7T-13 cells: Effects of cytokines and CCN family gene expression. Hepatol Res 37:1068-1079.
36. Hayashi, Y., Tsuji, S., Tsujii, M., Nishida, T., Ishii, S., Nakamura, T., Eguchi, H., and Kawano, S. 2007. The transdifferentiation of bone-marrow-derived cells in colonic mucosal regeneration after dextran-sulfate-sodium-induced colitis in mice. Pharmacology 80:193-199.
37. Lin, C.Y., Lee, B.S., Liao, C.C., Cheng, W.J., Chang, F.M., and Chen, M.H. 2007. Transdifferentiation of bone marrow stem cells into acinar cells using a double chamber system. J Formos Med Assoc 106:1-7.
Mr. Thomas Ichim, the CEO of Medistem has written a "state of the science" style column about stem cell therapy as it stands today.
Thomas Ichim is the CEO of Medistem Inc, Chairman of the Scientific Advisory Board of Orcrist Bio, and a Managing Partner of the Vendevia Group. Thomas has served a variety of oversight roles for companies operating in the area of biologics. He obtained numerous regulatory approvals for companies such as MarrowTech Pharma, and worked as a Program Director for the global CRO bioRASI (which he is a co-founder of), under which he led efforts to develop, clinically assess, and approve various stem cell and cellular therapies.
Ichim has also founded two companies, ToleroTech Inc. and MedVax Pharma Corp., which are developing proprietary technologies in the areas of RNA interference and cancer vaccines, respectively. As Managing Partner of Vendevia Group, he plays a pivotal role in new start-up formation, most recently in the establishment and financing of OncoMune, an epigenetic cancer therapy company. Ichim was an invitee to a recent government-sponsored California-Canada trade mission and has been instrumental in establishing Medistem's extensive collaborative network.
In addition to corporate responsibilities, Ichim is an accomplished scientist with numerous publications (>34 on pubmed), including his participation in the award-winning publication on the discovery of the ERC cells, the basis for Medistem's core products.
Ichim has created numerous videos discussing the state of stem cell clinical translation which can be seen at http://www.youtube.com/user/cellmedicine.
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The text of Mr. Ichim's column will be posted below. A PDF file has been attached as well.
_______________________________________________________
Adult Stem Cells: A Conversation With a Friend
I just had a telephone conversation with the brother of a spinal cord injury patient who was treated with stem cells in China. The brother, lets call him ?Matt? was a friend of a childhood friend of mine, so I could afford a certain degree of informality.
?Do stem cells actually become new nerve cells? How do the stem cells know how to communicate with the damaged cells? If stem cells really work, then why are they not approved in the US?? All of these are very potent questions. So when Barbara asked me to write a column on stem cell therapy, I figured it would only be proper to continue the conversation I had with Matt on a more elaborate basis for the audience of Stem Cell Pioneers. Since I am used to writing publications for medical journals, my experience in ?lay writing? is pretty minimal, therefore I ask you to be patient and if some of the points are not clear, please email your questions and I will be glad to answer them as best I can.
Tom what exactly are stem cells? How are they related to bone marrow transplants?
The field of ?stem cells? was born out of the work of Till and McCulloch who in the 1960s demonstrated one type of cell from the bone marrow could give rise to all of the cells of the blood system. This ability of the cell to make copies of itself, as well as to become different cell types, gained the name ?stem cell?. These stem cells, called ?hematopoietic stem cells?, are commonly used for treatment of cancer patients as part of ?bone marrow transplant? in which high doses of chemotherapy and/or radiation are given to patients, and the patient?s blood system is saved by administration of the donor stem cells. Since the first toxicity of healthy tissue is the blood making system, the ability to give higher levels of cytotoxic therapy allows for cures in some leukemias through transplantation of healthy stem cells. In addition to containing the cells that make blood, the bone marrow contains cells called ?stromal cells? that support the hematopoietic stem cells. Essentially, stromal cells are comprised of various actual cell populations The stroma includes adipocytes, osteoblasts, and mesenchymal stem cells (1). The primary function of mesenchymal stem cells in the bone marrow is to control proliferation of the hematopoietic stem cell, through provided growth factor support. This is why certain scientists are using mesenchymal stem cells to accelerate blood formation after administration of hematopoietic stem cells in patients (2).
So you are saying that there are two main types of adult stem cells, hematopoietic and mesenchymals? Right? Now what do they have to do with curing diseases, you only mentioned about the blood making system of the body.
Exactly. All of this ?stem cell? business started when scientists started studying the bone marrow and the incredible amount of new cells being made there. The next step of the stem cell revolution was when scientists started finding out that various cells from the bone marrow are capable of turning into, or ?differentiating? into other cells of the body. In the early scientific experiments, scientists didn?t distinguish between the bone marrow derived hematopoietic stem cells and mesenchymal stem cells, they simply took whole bone marrow and started injecting it into patients with various diseases (of course after they demonstrated activity in animal models). For example, in 2001 Strauer et al from Germany reported a case in which a 46 year old patient received his own (called ?autologous?) bone marrow cells by a catheter in the artery that was feeding the infracted area. 10 weeks after administration, the area damaged by the heart attack was reduced in size from 24.6 % to 15.7 % of left ventricular circumference. There was also a documented improvement in ejection fraction, cardiac index and stroke volume by 20-30 % (3). Placebo? Maybe, it was after all just one patient ! A subsequent paper in the same year reported administration of bone marrow cells in 5 patients with advanced heart failure undergoing coronary artery bypass grafting. The cells were administered intramuscularly into areas deemed ungraftable and perfusion was assessed by imaging. Specific improvement in areas injected was documented in 3 of the 5 patients. Perhaps more importantly, no growths of abnormal tissues or adverse effects were reported at 1 year follow-up (4). These two studies were important because they gave the suggestion that bone marrow stem cells may have a specific regenerative effect in tissues other than blood forming tissues.
OK, so in 2001 the ?great leap? was made from bone marrow making only blood, to bone marrow being able to fix up other tissues. But still this is only in a total of 6 patients. Means nothing.
Absolutely. But it did show one important point which was that in these situations the bone marrow cells do not become other tissues. For example, since bone marrow has stem cells and stem cells theoretically can become a wide variety of tissues, what if the stem cells became bone tissue? Or even non-functional muscle tissue in the heart?
Now let me address your point about significance. These pioneering studies in 2001 provided the ?comfort level? to investigators internationally to embark on numerous clinical trials using bone marrow stem cells for heart disease. I don?t want to go into details of every clinical trial performed with bone marrow stem cells, so let?s review some of the publications that summarize many of the clinical trials conducted.
The results of 999 patients treated in 18 independent controlled cardiac trials in which patients were treated with either unseparated bone marrow cells, bone marrow mesenchymal, or mobilized peripheral blood stem cells were reviewed by Abdel-Latif et (5). They found that overall in comparison to controls, there was a statistically significant improvement in ejection fraction, reduction in infarct size and left ventricular end-systolic volume. In another meta-analysis Martin-Rendon et al reviewed bone marrow therapy for post acute infarction trials. Of 13 randomized studies examined, encompassing 811 participants, the authors stated that more trials are needed to establish efficacy in terms of clinical endpoints such as death. However a consistent improvement in the heart?s pumping activity, as determined by LVEF, as well as trends for decrease in left ventricular end systolic and end diastolic volumes, and infarct size were noted (6). Two other major overviews of randomized trials in the area of bone marrow stem cell infusions also supported the conclusion of safety and mild but statistically significant improvement in LVEF (7, 8). These data suggest that stem cell therapy, both hematopoietic and mesenchymal have clinical effects in various types of heart failure. Theoretically the leap between these clinical trials and widespread implementation is more of a business question than a medical question.
So before I ask you about other diseases?let me first pose the question?if bone marrow stem cells actually have this therapeutic effect, why do we have to go to Mexico and China to get these treatments commercially? Why cant we just get them in North America?
For full-blown approval of therapeutics, the regulatory agency, whether it is the EMEA in Europe, or the FDA in the US, must review results of at least 2 Phase III double blind trials, and there must be a ?Sponsor? that promotes the therapy and offers it. Unfortunately, when there is little commercial incentive, this is difficult, if not impossible to do.
Can the FDA Accelerate Approval of Stem Cell Therapies?
Stem cell therapy offers hope in conditions which hope was previously unimaginable, however stem cell therapy is a brand new area. Remember, Marie Curie who discovered radioactivity died of leukemia (back then they didn?t know that radioactivity was so carcinogenic). Therefore while there is enormous potential in stem cell therapy, and thousands of people have been treated with stem cells without adverse events, this is a new area of exploration, which with big potential also may have substantial risks. The thalidomide tragedy was avoided in the US because of rigorous examination of the preclinical data.
So you mean that no money can be made from patients using their own bone marrow stem cells and that?s why they are not available commercially?
Well the problem is a bit more complicated. Firstly money can be made. Instead of using unpurified bone marrow, certain companies have figured out that the efficacy of bone marrow stem cells can be increased, at least theoretically, by purifying and concentrating the active ingredients in the bone marrow. For example, Baxter has developed a kit called ?Isolex? that purifies bone marrow CD34 positive stem cells. In March of 2006 Baxter began a Phase II clinical trial
Hold on?I keep hearing these words ?Phase I, Phase II, Phase III?, what does that mean?
The terminology originated in drug development and was adopted by celltherapists. Phase I is when the experimental agent is used in a dose escalating manner to identify the best dose.
How can you increase doses of cells without knowing what they are going to do? When do you stop increasing the dose?
Before Phase I, studies in animals are conducted, called ?preclinical studies? that give some level of approximation as to what doses would be safe in humans, and also what doses should be maximal. Maximal dose is either predetermined, or determined by a certain number of adverse events in the patients studied.
OK so Phase I determines dose, whats Phase II and III?
Phase II looks for efficacy with the dose selected from Phase I. Phase III is confirmation of efficacy, almost always in a double blind (neither doctor nor patient know what is being administered) manner and conducted in multiple centers.
Please continue about Baxter
Yes Baxter started a Phase II trial with their device in patients with chronic heart failure, but actually instead of drilling holes in the bone marrow to extract the stem cells, they give patients a drug that makes the stem cells leave the bone marrow and enter circulation, subsequently the stem cells are shipped to Baxter where the CD34 positive cells are purified and returned to the point of care for infusion into the patient
http://www.baxter.com/about_baxter/news_room/news_releases/2006/03-07-06-stem_cell_trial.html
Ok, so if this works with their system then they can charge money because that is something actually patentable?
Exactly. There is another form of stem cell therapy that is being commercialized. The problem with using your own stem cells comes from the fact that older stem cells do not work as well as younger stem cells, and also that patients that have cardiac risk factors usually have stem cells that work poorly. Therefore, some companies are developing stem cells that are ?universal donor? in other words, they do not need to come from the same individual that is receiving them.
One example of such ?universal donor? stem cells is the bone marrow derived mesenchymal stem cell. The mesenchymal stem cell looks different than the bone marrow blood forming (hematopoietic) stem cell. Specifically, mesenchymal stem cells attach to plastic and have an elongated shape, whereas hematopoietic stem cells are round and float when cultured. Another important difference is that mesenchymal stem cells do not make blood cells, instead, one of their primary functions in the bone marrow is to support the cells that make the blood cells.
If mesenchymal stem cells only support the cells that make blood cells, then why do we call them ?stem cells??
You are correct. Initially scientists believed that only the cells that make the blood cells are stem cells, however further investigations in the 1970s revealed that the ?sticky cells? could become bone and cartilage when treated with special chemicals. The stunning work of Arnold Caplan, whose patents went on to form the company Osiris, demonstrated that mesenchymal stem cells could become muscle and adipose tissue. Further work revealed that under certain conditions mesenchymal stem cells could even become neurons.
So what are mesenchymal stem cells useful for?
Well before I tell you that, I should state that since mesenchymal stem cells protect the blood forming stem cells, and since the blood forming stem cells are sensitive to even minute amounts of inflammation, the mesenchymal stem cells are potently anti-inflammatory. It is believed that this property, in part, is responsible for the ability of mesenchymal stem cells to be transplanted from one human to another without causing rejection.
Given that mesenchymal stem cells make bone and cartilage, these cells were used substantially for healing of injuries to these tissue. Mesenchymal stem cells from the fat, for example, have been used successfully in treating cartilage injuries in more than 1000 racehorses by the company Vet-Stem. Other studies in humans have demonstrated potent therapeutic effects of mesenchymal stem cells in conditions such as graft versus host (GVHD) (9-14), osteogenesis imperfecta (15), Hurler syndrome and metachromatic leukodystrophy (16). The company Osiris has successfully completed Phase I safety studies using mesenchymal stem cells and current conducting efficacy finding clinical trials (Phase II and Phase III) for Type I Diabetes, Crohn?s Disease, and Graft Versus Host Disease using allogeneic bone marrow derived MSC. Intravenous administration of allogeneic MSCs by Osiris was also reported to induce a statistically significant improvement in cardiac function in a double-blind study (17).
Other companies have entered clinical trials using mesenchymal stem cells, and cells similar to mesenchymal stem cells in the US. For example, the company Athersys is currently in Phase I trials using its MultiStem technology, which involves ex vivo expanded MAPC for post-infarct heart repair (18). Angioblast Systems has recently announced initiation of Phase II trials using Mesenchymal Precursor Cells for stimulation of cardiac angiogenesis (19). Neuronyx is in Phase I clinical trials using allogeneic human adult bone marrow-derived somatic cells (hABM-SC) for post infarct healing (20).
Second to bone marrow, another source of mesenchymal stem cells has been the adipose tissue. The company Cytori is currently conducting two European clinical trials using autologous adipose-derived mononuclear cells, of which MSC are believed to be the therapeutic population (21). The PRECISE trial is a 36-patient safety and feasibility study in Europe evaluating adipose-derived stem and regenerative cells as a treatment for chronic cardiac ischemia. The APOLLO trial is a 48-patient safety and feasibility study in Europe to evaluate adipose-derived regenerative cells as a treatment for heart attacks (22). Allogeneic uses of adipose derived MSC included treatment of graft versus host disease associated liver failure (23), and steroid refractory graft versus host disease (24, 25).
But I thought only embryonic stem cells could become different tissues and regenerate the body?
I don?t know?.there are a lot of arguments?but here are some examples of bone marrow cells becoming different tissues?
Some Examples of Bone Marrow Derived Stem Cells Becoming Different Tissue
Tissue Generated
Conditions Used
Institution
Reference
Neurons
Coculture of bone marrow with Swann Cells
Neuroscience Research Unit of the Mapfre Foundation, Madrid, Spain
(26)
Neurons
Neural induction media and Il-1
University of Medicine and Dentistry of New Jersey
(27)
Neurons
Sodium Ferulate
Jiangxi Medical College, Nanchang, China.
(28)
Neurons
Astrocyte conditioned media
University of Cagliari, Italy
(29)
Neurons
alpha-secretase-cleaved fragment of the amyloid precursor protein (sAPPalpha)
Mailman Research Center, McLean Hospital, 115 Mill Street, Belmont, MA USA
(30)
Neurons
NGF
Tel Aviv University,
(31)
Insulin Producing Cells
Nicotinamide containing cocktail
Nanjing Medical University
(32)
Insulin Producing Cells
Islet conditioned media
Centre Hospitalier Universitaire, Grenoble, France
(33)
Insulin Producing Cells
Histone deacetylase inhibitors
German Research Center for Biotechnology, Braunschweig, Germany
(34)
Liver
Fibroblast growth factors
Tottori University, Tottori, Japan.
(35)
Colonic Mucosa
In vivo injury
Osaka University Graduate School of Medicine
(36)
Salivary Glands
Co-culture with rat acinar cells
Graduate Institute of Clinical Dentistry, School of Dentistry, Taipei, Taiwan
(37)
So Tom, how do you fit into all of this?
Being CEO of Medistem, we work on a new type of stem cell deri@
?<Eometrium called the ?Endometrial Regenerative Cell? (ERC). These cells possess a very high activity to secrete growth factors. We use these cells in animal models because we are working at establishing enough data to file with the FDA.
What is Cellmedicine?
The Institute of Cellular Medicine (www.cellmedicine.com) is a clinical that licensed some of the technologies and know-how developed by Medistem. They treat patients with a variety of autologous adult stem cell based therapies.
Why would people go and get stem cell therapy at places like Cellmedicine when it is available in the US as part of clinical trials?
Many patients do not meet the inclusion/exclusion criteria to enter clinical trials. If you are interested, go to www.clinicaltrials.gov and search for ?stem cells?, you will see numerous ongoing trials here in the US. Other patients do not want to risk being the placebo control group.
So does stem cell therapy work?
Depends on the disease and the types of cells used. It is impossible to draw conclusions when 500 patients were treated but all the patients have different diseases and different stages of diseases. Randomized clinical trials are needed that are placebo controlled. These are currently ongoing or there are preparations for their initiation. The problem is that many patients do not want to wait until results come out to know for sure if the specific stem cell therapy works or doesn?t work.
Additionally, places like Cellmedicine (www.cellmedicine.com ) have a certain ability to offer individualized patient therapy based on the conditions and previous history of the patient. While this is good for the patient, it is not good for comparing patients side by side since everything is different.
References
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