Scleroderma is an autoimmune disease that causes chronic scarring of the skin and internal organs. The deposition of massive quantities of collagen decrease the pliability and elasticity of the skin, lungs, and blood vessels. As you might guess, the prognosis of scleroderma patients is quite poor and this disease causes a good deal of suffering and morbidity.
Treatments options usually include steroids, and other drugs that suppress the immune system, all of which have severe side effects.
New research from scientists at the Hospital for Special Surgery in New York City and other collaborating institutions, led by Dr. Teresa T. Lu, may have identified a new mechanism in operation during the onset and maintenance of scleroderma. This work was published in the Journal of Clinical Investigation.
In this study, scleroderma patients were shown to possess diminished numbers of “adipose-derived stromal cells” (ADSCs) in the layer of fat that underlies the upper layers of the skin. These fatty tissues are referred to as “dermal white adipose tissue.” The loss of these dermal white adipose tissue ADSCs tightly correlates with the onset of scarring in two different mouse model systems that recapitulate scleroderma in laboratory mice. These observations may show that ADSC loss contributes to scarring of the skin.
Why do these ADSCs die? Lu and her coworkers discovered that ADSC survival depends on the presence of particular molecules secreted by immune cells called “dendritic cells.” Skin-based dendritic cells secrete a molecule called lymphotoxin B. Although this molecule is called a toxin, it is required for ADSC survival. In laboratory mice that suffered from a scleroderma-like disease, artificial stimulation of the lymphotoxin B receptor in ADSCs amplified and eventually restored the numbers of ADSCs in the skin. Could stimulating ADSCs in this manner help treat scleroderma patients?
According the Dr. Lu, the administrating author of this publication, injecting “ADSCs is being tried in scleroderma; the possibility of stimulating the lymphotoxin B pathway to increase the survival of these stem cells is very exciting.” Dr. Lu continued, “By uncovering these mechanisms and targeting them with treatments, perhaps one day we can better treat the disease.”
Lu also thinks that a similar strategy that targets stem cells from other tissues might provide a treatment for other rheumatological conditions – such as systemic lupus erythematosis and rheumatoid arthritis. Additionally, bone and cartilage repair might also benefit from such a treatment strategy.
In the coming years, Dr. Lu and her colleagues hope to test the applicability of this work in human cells. If such a strategy works in human cells, then the next stop would be trial in human scleroderma patients. The success of such a treatment strategy would be a welcome addition to the treatment options for scleroderma patients, but only if this treatment is shown to be proven safe and effective.
“Improving ADSC therapy would be a major benefit to the field of rheumatology and to patients suffering from scleroderma,” said Lu.
New preclinical experiments by scientists at the University of Pennsylvania have established that genetically engineered T-cells can drive severe autoimmune diseases into remission without suppressing the patient’s immune system. If the principles applied in this study also prove to be true in human patients, they can potentially revolutionize the treatment of autoimmune diseases.
Autoimmune diseases result when your immune system recognizes your own cells and tissues as foreign and mounts and immune response against them. Autoimmune diseases like systemic lupus erythematosus (also known as “lupus”), rheumatoid arthritis, scleroderma, multiple sclerosis, celiac disease, Sjögren’s syndrome, polymyalgia rheumatic, or ankylosing spondylitis can deeply affect the health of an individual and can also cause large amounts of tissue damage.
Treatment of autoimmune diseases usually requires high doses of drugs that suppress the immune system, such as corticosteroids, or various types of biological agents that also cause a host of undesirable side effects.
This new study, however, by scientists from the Perelman School of Medicine at the University of Pennsylvania have adapted an already-existing technology to remove the subset of antibody-making cells that cause the autoimmune disease. This strategy removes the rogue immune cells without harming the rest of the immune system.
In these experiments, the University of Pennsylvania team examined an autoimmune disease called pemphigus vulgaris or PV. PV results when the immune system recognizes a protein called desmoglein-3 (Dsg3) as foreign and attacks it. Dsg3 helps form attachment sites called “desmosomes” that normally adhere skin cells together to form tight, tough sheets. Desmosomes are also found between epithelial cells, myocardial cells, and other cell types.
Current therapies for autoimmune diseases like PV use drugs like prednisone and rituximab, which suppress large parts of the immune system. Consequently, prednisone and rituximab can leave patients vulnerable to potentially fatal opportunistic infections and cancers.
To treat PV, University of Pennsylvania researcher Aimee Payne and her colleagues used a mouse version of PV that is fatal in mice. Their experimental treatment, however, successfully treated this otherwise fatal autoimmune disease without causing any unintended side effects, which might harm healthy tissue. The results from these experiments were published in the journal Science.
“This is a powerful strategy for targeting just autoimmune cells and sparing the good immune cells that protect us from infection,” said Dr Payne, who serves as the Albert M. Kligman Associate Professor of Dermatology at the Perelman School of Medicine.
In collaboration with Dr. Michael Milone, assistant professor of Pathology and Laboratory Medicine, Payne and her colleagues adapted the Chimeric Antigen Receptor T-Cell (CART-Cell) technology that is being successfully used to experimentally treat malignant cells in certain leukemias and lymphomas. “Our study effectively opens up the application of this anti-cancer technology to the treatment of a much wider range of diseases, including autoimmunity and transplant rejection,” Milone said.
CART-Cells are T-lymphocytes that have been extracted from the peripheral blood of cancer patients and then genetically engineered to express a receptor that specifically recognizes a protein on the surface of tumor cells. These chimeric antigen receptor (CAR)-expressing cytotoxic T-lymphocytes have the ability to recognize and destroy tumor cells, which shrinks the tumor and potentially cures the patient.
The core concepts behind CAR T-cells were first described in the late 1980s. Unfortunately, technical challenges prevented the development of this technology until later. However, since 2011, experimental CAR T cell treatments for B cell leukemias and lymphomas have been successful in some patients for whom all standard therapies had failed.
Antibody-producing B-lymphocytes or B-cells can also cause autoimmunity. A few years ago, a postdoctoral researcher in Payne’s laboratory named Dr. Christoph T. Ellebrecht came upon CAR T cell technology as a potential strategy for deleting rogue B-cells that make antibodies against a patient’s own tissues. Soon Payne and her team had teamed up with Milone’s, which studies CAR T cell technology. Their goal was to find a new way to treat autoimmune diseases.
“We thought we could adapt this technology that’s really good at killing all B cells in the body to target specifically the B cells that make antibodies that cause autoimmune disease,” said Milone.
“Targeting just the cells that cause autoimmunity has been the ultimate goal for therapy in this field,” noted Payne.
Because an excellent mouse model existed for PV, Payne and Milone decided to examine pemphigus vulgaris. Since PV consists of a patient’s antibodies attacking those molecules that normally keep skin cells together, it can cause extensive skin blistering and is almost always fatal. PV is treatable with broadly immunosuppressive drugs such as prednisone, mycophenolate mofetil, and rituximab.
However, to treat PV without causing broad immunosuppression, the Penn team designed an artificial CAR-type receptor that would home the patient’s own genetically engineered T-cells exclusively to those B-cells that produce harmful anti-Dsg3 antibodies.
Payne and Milone and their colleagues developed a “chimeric autoantibody receptor,” or CAAR, that displays fragments of the Dsg3 on their cell surfaces. Since the Dsg3 protein is the target of the PV-causing B-cells, the CAAR acts as a lure for the rogue B cells that target Dsg3. The CAAR effectively brings the cells into fatal contact with the therapeutic T cells.
After testing a battery of different cultured, genetically engineered T-cells, these teams eventually found a CAAR that worked well in cell culture and enabled host T cells to efficiently destroy anti-desmoglein-producing B-cells. These cultured cells worked so well that they even killed B-cells isolated from PV patients. The engineered CAAR T cells also performed successfully in a mouse model of PV. The CAAR T-cell effectively killed desmoglein-specific B cells, prevented blistering, and other manifestations of autoimmunity in the animals. “We were able to show that the treatment killed all the Dsg3-specific B cells, a proof of concept that this approach works,” Payne said.
Not only were these treatments devoid of undesirable side effects in the laboratory mice they studied, but they maintained their potency despite the presence of high levels of anti-Dsg3 antibodies that might have swamped out their CAARs.
Next, Payne plans to test her treatment in dogs, which can also develop PV and often die from it. “If we can use this technology to cure PV safely in dogs, it would be a breakthrough for veterinary medicine, and would hopefully pave the way for trials of this therapy in human pemphigus patients,” Payne said.
Penn scientists would also like to develop applications of CAAR T cell technology for other types of autoimmunity. Organ transplant rejection, which is also related to autoimmunity, complicates organ transplants, and normally requires long-term immunosuppressive drug therapy, may also be treatable with CAAR T cell technology.
“If you can identify a specific marker of a B cell that you want to target, then in principle this strategy can work,” Payne said.
The Belgium-based biotechnology company, TiGenix, has launched a clinical trial entitled SEPCELL that uses fat-derived stem cells (called Cx611) to treat severe sepsis secondary to acquired pneumonia (also known as sCAP). SEPCELL is a randomized, double-blind, placebo-controlled, Phase 1b/2a study of sCAP patients who require mechanical ventilation and/or vasopressors.
SEPCELL will, hopefully, enroll 180 patients and will be conducted at approximately 50 centers throughout Europe. Subjects who participate in this trial will be randomly assigned to receive either an investigational product or placebo on days 1 and 3. All patients will be treated with standard care, which usually includes broad-spectrum antibiotics and anti-inflammatory drugs.
The primary endpoint of this clinical trial will examine the number, frequency, and type of adverse reactions during the 90-day period of the trial. The secondary endpoints of the SEPCELL trial include reduction in the duration of mechanical ventilation and/or vasopressors, overall survival, clinical cure of sCAP, and other infection-related endpoints. SEPCELL will also assess the safety and efficacy of the expanded allogeneic adipose stem cells (eASCs) that will be intravenously delivered to some of the patients in this study.
The SEPCELL trial will be managed by TFS International, a company based in Lund, Sweden. TFS has extensive experience in running sepsis trials and hospital-based trials.
Sepsis is a potentially life-threatening complication of infection that occurs when inflammatory molecules (cytokines and chemokines) released into the bloodstream to fight the infection trigger systemic inflammation. This body-wide inflammation has the ability to trigger a cascade of detrimental changes that damage multiple organ systems and cause them to fail. If sepsis progresses to “septic shock,” blood pressure drops dramatically, which may lead to death. Patients with “severe sepsis” require close monitoring and treatment in a hospital intensive care unit. Drug therapy is likely to include broad-spectrum antibiotics, corticosteroids, vasopressor drugs to increase blood pressure, as well as oxygen and large amounts of intravenous fluids. Supportive therapy may be needed to stabilize breathing and heart function and to replace kidney function. Patients with severe sepsis have a low survival rate so there is a critical need to improve the effectiveness of current therapy. Only a small number of new molecular entities are currently in development for severe sepsis.
Severe sepsis and septic shock significantly affect public health and these event also are leading causes of mortality in intensive care units.
Severe sepsis and septic shock have an incidence of about 3 cases per 1,000, but due to the aging of the population and an increase in drug resistant bacteria.
Cx611 is an intravenously-administered concoction that consists of allogeneic eASCs. These cells are largely mesenchymal stem cells that secrete an impressive array of molecules that suppress the type of immune responses that damage organs during events like septic shock. eASCs have a higher proliferation rate in culture and faster attachment than bone marrow-based mesenchymal stem cells in cell culture. ASCs are also less prone to senescence and differentiation. Their differentiation capacity decreases with expansion time without losing immunomodulatory properties. These eASCs also have superior inflammation targeting capacities than bone marrow-based mesenchymal stem cells, and are safe, since they do not express ligands for receptors on Natural Killer cells that, and therefore, are unlikely to elicit an immune rejection.
In May 2015, TiGenix completed a Phase 1 sepsis challenge that demonstrated that Cx611 is safe and well tolerated. That trial began in December 2014, and was a placebo-controlled dose-ranging study (3 doses of eASC’s) in which 32 healthy male volunteers were randomized to receive Cx611 or placebo in a ratio of 3:1. Primary endpoints were vital signs and symptoms, laboratory measures and functional assays of innate immunity. All 32 volunteer subjects were recruited and dosed by March 2015. By May, 2015, the phase I trial data essentially demonstrated the safety and tolerability of Cx611. On the strength of that phase I trial, TiGenix designed a Phase 1b/2a trial in severe sepsis secondary to sCAP in which they expecet to enroll 180 subjects across Europe.
SEPCELL was funded by a €5.4 million grant ($6.14 million) from the European Union.
Patients with Crohn’s disease (CD) sometimes suffer from daily bouts of stomach pain and diarrhea. These constant gastrointestinal episodes can prevent them from absorbing enough nutrition to meet their needs, and, consequently, they can suffer from weakness, fatigue, and a general failure to flourish.
To treat Crohn’s disease, physicians use several different types of drugs. First there are the anti-inflammatory drugs, which include oral 5-aminosalicylates such as sulfasalazine (Azulfidine), which contains sulfur, and mesalamine (Asacol, Delzicol, Pentasa, Lialda, Apriso). These drugs, have several side effects, but on the whole are rather well tolerated. If these don’t work, then corticosteroids such as prednisone are used. These have a large number of side effects, including a puffy face, excessive facial hair, night sweats, insomnia and hyperactivity. More-serious side effects include high blood pressure, diabetes, osteoporosis, bone fractures, cataracts, glaucoma and increased chance of infection.
If these don’t work, then the stronger immune system suppressors are brought out. These drugs have some very serious side effects. Azathioprine (Imuran) and mercaptopurine (Purinethol) are two of the most widely used of this group. If used long-term, these drugs can make the patient more susceptible to certain infections and cancers including lymphoma and skin cancer. They may also cause nausea and vomiting. Infliximab (Remicade), adalimumab (Humira) and certolizumab pegol (Cimzia) are the next line of immune system suppressors. These drugs are TNF inhibitors that neutralize an immune system protein known as tumor necrosis factor (TNF). These drugs are also associated with certain cancers, including lymphoma and skin cancers. The next line of drugs include Methotrexate (Rheumatrex), which is usually used to treat cancer, psoriasis and rheumatoid arthritis, but methotrexate also quells the symptoms of Crohn’s disease in patients who don’t respond well to other medications. Short-term side effects include nausea, fatigue and diarrhea, and rarely, it can cause potentially life-threatening pneumonia. Long-term use can lead to bone marrow suppression, scarring of the liver and sometimes to cancer. You will need to be followed closely for side effects.
Then there are specialty medicines for patients who do not respond to other medicines or who suffer from openings in their lower large intestines to the outside world (fistulae). These include cyclosporine (Gengraf, Neoral, Sandimmune) and tacrolimus (Astagraf XL, Hecoria). These have the potential for serious side effects, such as kidney and liver damage, seizures, and fatal infections. These medications are definitely cannot be used for long period of time as their side effects are too dangerous.
If the patient still does not experience any relief, then two humanized mouse monoclonal antibodies natalizumab (Tysabri) and vedolizumab (Entyvio). Both of these drugs bind to and inhibit particular cell adhesion molecules called integrins, and in doing so prevent particular immune cells from binding to the cells in the intestinal lining. Natalizumab is associated with a rare but serious risk of a brain disease that usually leads to death or severe disability called progressive multifocal leukoencephalopathy. In fact, so serious are the side effects of this medicine that patients who take this drug must be enrolled in a special restricted distribution program. The other drug, vedolizumab, works in the same way as natalizumab but does not seem to cause this brain disease. Finally, a drug called Ustekinumab (Stelara) is usually used to treat psoriasis. Studies have shown it’s useful in treating Crohn’s disease and might useful when other medical treatments fail. Ustekinumab can increase the risk of contracting tuberculosis and an increased risk of certain types of cancer. Also there is a risk of posterior reversible encephalopathy syndrome. More common side effects include upper respiratory infection, headache, and tiredness.
The ASTIC trial enrolled 45 Crohn’s disease patients, all of whom underwent stem cell mobilization with cyclophosphamide and filgrastim, and were then randomly assigned to immediate stem cell transplantation (at 1 month) or delayed transplantation (at 13 months; control group). Blood samples were drawn and mobilized stem cells were isolated from the blood. In twenty-three of these patients, their bone marrow was partially wiped out and reconstituted by means of transplantations with their own bone marrow stem cells. The other 22 patients were given standard Crohn disease treatment (corticosteroids and so on) as needed.
The bad news is that hematopoietic stem cell transplantations (HSCT) were not significantly better than conventional therapy at inducing sustained disease remission, if we define remission as the patient not needing any medical therapies (i.e. drugs) for at least 3 months and no clear evidence of active disease on endoscopy and GI imaging at one year after the start of the trial. All patients in this study had moderately to severely active Crohn’s disease that was resistant to treatment, had failed at least 3 immunosuppressive drugs, and whose disease that was not amenable to surgery. All participants in this study had impaired function and quality of life. Also, the stem cell transplantation procedure, because it involved partially wiping out the bone marrow, cause considerable toxicities.
Two patients who underwent HSCT (8.7%) experienced sustained disease remission compared to one control patient (4.5%). Fourteen patients undergoing HSCT (61%) compared to five control patients (23%) had discontinued immunosuppressive or biologic agents or corticosteroids for at least 3 months. Eight patients (34.8%) who had HSCTs compared to two (9.1%) patients treated with standard care regimens were free of the signs of active disease on endoscopy and radiology at final assessment.
However, there were 76 serious adverse events in patients undergoing HSCT compared to 38 in controls, and one patient undergoing HSCT died.
So increased toxicities and not really a clear benefit to it; those are the downsides of the ASCTIC study. An earlier report of the ASTIC trial in 2013, while data was still being collected and analyzed was much more sanguine. Christopher Hawkey, MD, from the University of Nottingham in the United Kingdom said this: “Some of the case reports are so dramatic that it’s reasonable to talk about this being a cure in those patients.” These words came from a presentation given by Dr. Hawkey at Digestive Disease Week 2013. Further analysis, however, apparently, failed to show a clear benefit to HSCT for the patients in this study. It is entirely possible that some patients in this study did experience significant healing, but statistically, there was no clear difference between HSCT and conventional treatment for the patients in this study.
The silver lining in this study, however, is that compared to the control group, significantly more HSCT patients were able to stop taking all their immunosuppressive therapies for the three months prior to the primary endpoint. That is a potential upside to this study, but it is unlikely for most patients that this upside is worth the heightened risk of severe side effects. An additional potential upside to this trial is that patients who underwent HSCT showed greater absolute reduction of clinical and endoscopic disease activity. Again, it is doubtful if these potential benefits are worth the higher risks for most patients although it might be worth it for some patients.
Therefore, when HSCT was compared with conventional therapy, there was no statistically significant improvement in sustained disease remission at 1 year. Furthermore, HSCT was associated with significant toxicity. Overall, despite some potential upside to HSCT observed in this study, the authors, I think rightly, conclude that their data do not support the widespread use of HSCT for patients with refractory Crohn’s disease.
Could HSCT help some Crohn’s patients more than others? That is a very good question that will need far more work with defined patient populations to answer. Perhaps further work will ferret out the benefits HSCT has for some Crohn’s disease patients relative to others.
The ASTIC trial was a collaborative project between the European Society for Blood and Marrow Transplantation (EBMT) and the European Crohn’s and Colitis Organization (ECCO) and was funded by the Broad Medical Foundation and the Nottingham Digestive Diseases Centers.
Systemic Lupus Erythematosis, otherwise known as lupus, is an autoimmune disease cause your own immune system attacking various cells and tissues in your body. Lupus patients can suffer from fatigue, joint pain and selling and show a marked increased risk or osteoporosis.
Clinical trials have established that infusions of mesenchymal stem cells (MSCs) can significantly improve the condition of lupus patients, but exactly why these cells help these patients is not completely clear. Certainly suppression of inflammation is probably part of the mechanism by which these cells help lupus patients, but how do these cells improve the bone health of lupus patients?
Songtao Shi and his team at the University of Pennsylvania have used an animal model of lupus to investigate this very question. In their hands, transplanted MSCs improve the function of bone marrow stem cells by providing a source of the FAS protein. FAS stimulates bone marrow stem cell function by means of a multi-step, epigenetic mechanism.
This work by Shi and his colleagues has implications for other cell-based treatment strategies for not only lupus, but other diseases as well.
“When we used transplanted stem cells for these diseases, we didn’t know exactly what they were doing, but saw that they were effective,” said Shi. “Now we’ve seen in a model of lupus that bone-forming mesenchymal stem cell function was rescued by a mechanism that was totally unexpected.”
In earlier work, Shi and his group showed that mesenchymal stem cell infusions can be used to treat various autoimmune diseases in particular animals models. While these were certainly highly desirable results, no one could fully understand why these cells worked as well as they did. Shi began to suspect that some sort of epigenetic mechanism was at work since the infused MSCs seemed to permanently recalibrate the gene expression patterns in cells.
In order to test this possibility, Shi and others found that lupus mice had a malfunctioning FAS protein that prevented their bone marrow MSCs from releasing pro-bone molecules that are integral for bone maintenance and deposition.
A deficiency for the FAS protein prevents bone marrow stem cells from releasing a microRNA called miR-29b. The failure to release miR-29b causes its concentrations to increase inside the cells. miR-29b can down-regulate an enzyme called DNA methyltransferase 1 (Dnmt1), and the buildup of miR-29b inhibits Dnmt1, which causes decreased methylation of the Notch1 promoter and activation of Notch signaling. Methylation of the promoters of genes tends to shut down gene expression, and the lack of methylation of the Notch promoter increases Notch gene expression, activating Notch signaling. Unfortunately, increased Notch signaling impaired the differentiation of bone marrow stem cells into bone-making cells. Transplantation of MSCs brings FAS protein to the bone marrow stem cells by means of exosomes secreted by the MSCs. The FAS protein in the MSC-provided exosomes reduce intracellular levels of miR-29b, which leads to higher levels of Dnmt1. Dnmt1 methylates the Notch1 promoter, thus shutting down the expression of the Notch gene, and restoring bone-specific differentiation.
Shi and others are presently investigating if this FAS-dependent process is also at work in other autoimmune diseases. If so, then stem cell treatments might convey similar bone-specific benefits.
GVHD occurs when newly transplanted donor cells attack the recipient’s body. It can occur after a bone marrow or stem cell transplant if the cells have not been properly matched or even if the donor and recipient are relatively well matched. The chances of suffering GVHD are around 30 – 40% if the donor and recipient are genetically related and close to 60 – 80% when the donor and recipient are not related.
GVHD can be either acute or chronic and the symptoms of GvHD can be either mild or severe. Typically, acute GVHD comes on within the first 6 months after a transplant. Common acute symptoms include: Abdominal pain or cramps, nausea, vomiting, and diarrhea, Jaundice (yellow coloring of the skin or eyes) or other liver problems, skin rash, itching, redness on areas of the skin. Chronic GVHD usually starts more than 3 months after a transplant, and can last for the lifetime or the patient. The symptoms of chronic GvHD include: dry eyes or vision changes, dry mouth, white patches inside the mouth, and sensitivity to spicy foods, fatigue, muscle weakness, and chronic pain, joint pain or stiffness, skin rash with raised, discolored areas, as well as skin tightening or thickening, shortness of breath, weight loss.
Endonovo uses a novel method to enhance stem cells. Their so-called “Cytotronics platform” utilizes Time-Varying Electromagnetic Field (TVEMF) technology to expand and enhance the therapeutic properties of stem cells and other types of cells for regenerative treatments and tissue engineering. This platform can potentially optimize cell-based therapies so that they have greater therapeutic potential than they had prior to their treatment.
The Cytotronics™ platform dates back to experiments conducted at NASA to expand stem cells in culture. NASA’s goal was to create stem cell therapies that could be used to treat astronauts during long-term space exploration. NASA scientists showed that Time-Varying Electromagnetic Fields (TVEMF) could stimulate the expansion of stem cells in the lab. Additionally, TVEMF increased the expression of dozens of genes related to cell growth, tumor suppression, cell adhesion and extracellular matrix production.
By testing and tweaking this technology over a period of 15 years, Endonovo scientists created a novel protocol for augmenting the therapeutic properties of cells in culture through physics rather than genetic engineering. The Cytotronics™ platform seems to be able to make stem cells that express higher levels of key genes necessary for tissue healing and regeneration.
As an example of the efficacy of this technology. Endonovo scientists have shown that Cytotronic™ expansion of peripheral blood stem cells resulted in an over 80-fold expansion of CD34+ cells in as little as 6 days.
Endonovo is using the Cytotronic platform to enhance the regenerative properties of mesenchymal stem cells (MSCs), which have the capacity to staunch inflammation in patients with GvHD and other inflammatory diseases.
However, despite their promise, MSC-based therapies suffer from poor engraftment and short-term survival when transplanted into sick patients. These remain major limitations to the effective therapeutic use of MSCs. If there was a safe and effective way to beef up the survival and regenerative properties of MSCs, such a technique would be indispensable. This makes MSCs prime candidates for the Cytotronic Platform.
Dr. Donnie Rudd, Chief Scientist & Director of Intellectual Property at Endonovo, said: “Our Cytotronics platform is particularly suited to address many of the issues that have plagued stem cell therapies that have recently failed, such as their loss of potency and self-renewal when expanded ex vivo, their poor engraftment and their limited ability to survive when transplanted.”
Earlier this year, Endonovo announced a protocol for the creation of a cell mixture from a portion of the human umbilical cord co-cultured with adipose-derived stem cells. This resulting cell mixture contains a rich source of highly-proliferative, immunosuppressive cells that are not recognized by the patients immune system, since they contain neither of the major histocompatibility markers (HLA double negative). These cells are “immune privileged,” which means that are not recognized as foreign cells by the patient’s immune system, and therefore are a significant source of cells for MSC-based therapies.
Endonovo Therapeutics has used this new technology to create a biologically potent, off-the-shelf, allogeneic treatment for Graft-Versus-Host disease and a wide-array of other conditions. They would like to test these products in clinical trials eventually.
Endonovo hopes that stem cells enhanced by the Cytotronics™ platform will become a major innovation in the regenerative medicine market.
“We are very excited to be a leader in the development of next-generation, ex vivo enhanced cells for regenerative medicine,” stated Endonovo CEO, Alan Collier. “We have seen several stem cell therapies fail in clinical trials over the last couple of years, which points to a critical need for the development of methods to increase the biological and therapeutic properties of stem cells.”
“We believe that enhancing the biological and therapeutic properties of stem cells using bioelectronics is the future of cell-based therapies,” concluded Mr. Collier.
Multiple Sclerosis (MS) is a debilitating autoimmune disease in which the immune system attacks elements of the central nervous system. There are different types of MS, but more progressive cases can leave patients unable to walk and may require rather extreme immunosuppressive treatments that can predispose a patient to illness and cancer.
However, a new study that was published in the journal Neurology has shown that stem cell transplantation could be a more effective therapy in severe cases of multiple sclerosis (MS) than the drug mitoxantrone.
Mitoxanthone is a “type II topoisomerase inhibitor” that disrupts DNA synthesis and DNA repair by inserting between the bases in DNA. Mitoxanthone can cause nausea, vomiting, hair loss, heart damage, and suppression of the immune system. Some side effects may have delayed onset. Heart damage (cardiomyopathy) is a particularly concerning effect with this drug, since it is irreversible. Therefore, because of the risk of cardiomyopathy, mitoxantrone carries a limit on the cumulative lifetime dose, which is based on the body surface area of patients.
Because MS is an immune-mediated disorder, and because immune cells are made by stem cells in the bone marrow, bone marrow transplants (hematopoietic stem cell transplantation), which are routinely used in the treatment of leukemia and lymphoma, are being considered as a treatment for MS.
A clinical trial conducted by Giovanni Mancardi from the University of Genova, Italy designed a randomized phase II clinical trial study that included 21 MS patients, whose average age was 36 and whose disability due to the disease had worsened in the previous year despite the fact that the patients were under conventional medication treatment. The average disability level of the participants was represented by the need of a crutch or cane to walk. The goal of the study was to determine the efficacy of intense immunosuppression followed by either a bone marrow transplant with the patient’s own bone marrow, or mitoxantrone (MTX) in MS disease activity.
All participants in this clinical trial received immune-suppressive medication. MTX was given to 12 of the patients while the remaining 9 received hematopoietic stem cells harvested from their own bone marrow. After treatment with MTX, the stem cells were intravenously reintroduced into their donors and the stem cells migrated back to the bone marrow where they generated new immune cells. All participants were followed-up for a period of up to four years after their treatment.
“This process appears to reset the immune system,” said the lead study author Dr. Giovanni Mancardi. “With these results, we can speculate that stem cell treatment may profoundly affect the course of the disease.”
Mancardi and his team found that treatment of MS patients with robust immunosuppression followed by stem cell treatment resulted in a significantly higher decrease in disease progression in comparison with MTX treatment alone. MS patients under stem cell treatment reduced the number of new areas of brain damage (T2 lesions) by 79% compared to patients under MTX treatment. Another type of lesion seen in MS patients – gadolinium-enhancing lesions – were not detected in patients under stem cell treatment during the study, whereas 56% of patients receiving MTX exhibited at least one new gadolinium-enhancing lesion.
Mancardi and his team concluded that an intense immunosuppression followed by autologous hematopoietic stem cell transplantation is more efficient than MTX to reduce MS activity in severe cases.
“More research is needed with larger numbers of patients who are randomized to receive either the stem cell transplant or an approved therapy, but it’s very exciting to see that this treatment may be so superior to a current treatment for people with severe MS that is not responding well to standard treatments,” concluded study author Dr. Mancardi.
Ever since they were first isolated, amnion-based stem cells have been considered promising candidates for cell therapies because of their ease of access, plasticity, and absence of ethical issues in their derivation and use. However, a Japanese research team has discovered that stem cells derived from human female amnion also have the ability to suppress the inappropriate activation of the immune system and that there are straight-forward ways to enhance their immunosuppressive potential.
The amniotic membrane is a three-layered structure that surrounds the baby and suspends it in amniotic fluid. Amniotic fluid acts as a protective shock-absorber, a lubricant and an important physiological player in the life of the embryo and fetus. Because the fetus is a privileged entity that escapes attack from the mother’s immune system, researchers have been very interested in determining the immunological properties of the amnion cells.
“The human amniotic membrane contains both epithelial cells and mesenchymal cells,” said study co-author Dr. Toshio Nikaido, Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences at the University of Toyama. “Both kinds of cells have proliferation and differentiation characteristics, making the amniotic membrane a promising and attractive source for amnion-derived cells for transplantation in regenerative medicine. It is clear that these cells have promise, although the mechanism of their immune modulation remains to be elucidated.”
In this study by Nikaido and his coworkers, amnion-derived cells inhibited natural killer cell activity and induced white blood cell activation. Nikaido reported that he and his colleagues saw the amnion-derived cells increase production of a molecule called interleukin-10 (IL-10).
“We consider that IL-10 was involved in the function of amnion-derived cells toward NK cells,” explained Dr. Nikaido. “The immunomodulation of amnion-derived cells is a complicated procedure involving many factors, among which IL-10 and prostaglandin E2 (PGE2) play important roles.”
Molecules called “prostaglandins,” such as PGE2, mediate inflammation, smooth muscle activity, blood flow, and many other physiological process. In particular, PGE2 exerts important effects during labor and stimulates osteoblasts (bone-making cells) to release factors that stimulate bone resorption by osteoclasts. PGE2 also suppresses T cell receptor signaling and may play a role in the resolution of inflammation.
When Nikaido and others used antibodies against PGE2 and IL-10, they removed the immunosuppressive effects of the amnion-derived cells on natural killer cells. These data imply that these two factors contribute to the immunosuppressive abilities of amnion-derived cells.
“Soluble factors IL-10 and PGE2 produced by amnion-derived cells may suppress allogenic, or ‘other’ related immune responses,” concluded Dr. Nikaido. “Our findings support the hypothesis that these cells have potential therapeutic use. However, further study is needed to identify the detailed mechanisms responsible for their immodulatory effects. Amnion-derived cells must be transplanted into mouse models for further in vivo analysis of their immunosuppressive activity or anti-inflammatory effects.”
Given the levels of autoimmune diseases on the developed world, these results could be good news for patients who suffer from diseases like Crohn’s disease, systemic lupus erythematosus, or rheumatoid arthritis. While more work is needed, amnion-based cells certainly show promise as immunosuppressive agents.
Stiff-Person syndrome is a rare neurological disease that, for all intents and purposes, looks like an autoimmune disease. It is characterized by muscular rigidity that tends to come and go. This rigidity occurs in the muscles of the trunks and limbs. Patients with Stiff-Person syndrome also have an enhanced sensitivity to stimuli such as noise, touch, and emotional distress, and various stimuli may cause the patient to experience painful muscle spasms that cause abnormal postures and stiffening. Stiff-Person syndrome or SPS is more common in women than in men and SPS patients often suffer from other autoimmune conditions in addition to SPS (for example, pernicious anemia, diabetes, vitiligo, and thyroiditis). Unfortunately, the precise cause of SPS is not known, but again, it looks like an autoimmune condition.
A research team at Ottawa Hospital Research Institute has made a breakthrough in the successful treatment of SPS using bone marrow stem cell transplants. The medical director at the Ottawa Hospital Research Institute, Dr. Harold L. Atkins, who is also a physician in the Blood and Bone Marrow Transplant Program at The Ottawa Hospital and an associate professor at the University of Ottawa has used bone marrow transplants to two female SPS patients into remission.
SPS can leave patients bedridden and in severe pain, but thanks to Atkins and his team, the progression of the disease in these women has ceased, allowing both women to regain their previous function and leaving them well enough to return to work and normal everyday activities.
Adkins and his group published this case study in JAMA Neurology, which is produced by the Journal of the American Medical Association. This is the first documented report that taking stem cells from a person’s own body can produce long-lasting remission of stiff person syndrome.
“We approach these cases very carefully and are always aware that there have just been a few patients treated and followed for a short time,” says Dr. Atkins. Atkins and his extracted bone marrow stem cells from each woman, and then used chemotherapy to eliminate their immune systems. Once their immune system were reliably eliminated, both women had their own stem cells returned to their bodies in order to reconstitute their immune systems. This procedure essentially gives the immune system a “do-over.”.
“By changing the immune system, one hopes to put the stiff person syndrome into remission,” adds Dr. Atkins. “Seeing these two patients return to their normal lives is really every physicians dream.”
This very procedure, which is known as an “autologous stem cell transfer” or ASCT has been used to successfully treat people who suffer from autoimmune diseases such as multiple sclerosis, scleroderma, and systemic lupus erythematosis. Atkins and his team used high-doses of chemotherapy and antibodies that specifically bind lymphocytes to rid the women’s bodies of their rogue immune cells before their immune systems were regenerated using their own stem cells. Adkins an his colleagues viewed this as a viable treatment option based strategies that had been used to treat other autoimmune diseases.
Patient 1 was diagnosed with stiff person syndrome in 2005 at age 48 after experiencing leg stiffness and several falls. After her treatment, her symptoms disappeared and she was fully mobile again six months after receiving the stem cell transplant procedure in 2009.
Patient 2 was diagnosed with stiff person syndrome in 2008 at age 30. She had stopped working and driving, and had moved back in with her parents before her stem cell transplant in 2011. Also, she has been able to return to her work and previous activities, and has not had any stiff person syndrome symptoms in more than a year.
“The results achieved by Dr. Atkins and his team through this innovative treatment show how research at The Ottawa Hospital can lead to life-changing and, even life-saving care,” says Dr. Duncan Stewart, Chief Executive Officer and Scientific Director of the Ottawa Hospital Research Institute. “Translating research into better care for patients is what we’re all about at the research institute.”
Ulcerative colitis is one of the Inflammatory Bowel Diseases (IBDs) that features chronic inflammation of the large intestine. This is an autoimmune disease that features constant attacks by the immune system on the intestinal mucosae, and the inner layer of the large intestine undergoes constant damage and healing, which increases the risk of the patient to developing colorectal carcinoma.
Mesenchymal stem cells have the capability to suppress inflammation, which makes them promising tools for treating diseases like ulcerative colitis. Unfortunately, the lack of reproducible techniques for harvesting and expanding MSCs has prevented bone marrow- and umbilical cord blood-derived MSCs from being routinely used in clinical situations.
However, a study that was published in the journal Clinical and Experimental Pharmacology and Physiology has used Wharton’s jelly derived umbilical MSCs (UMSCs) to treat mice in which an experimental form of ulcerative colitis was induced. Dextran sulfate sodium (DSS) induced colitis in mice has many of the pathological features of ulcerative colitis in humans.
When mice treated with DSS were also given Wharton’s jelly derived UMSCs showed significant diminution of the severity of colitis. The structure of the tissue in the colon looked far more normal and the types of molecules produced by inflammation were significantly reduced. In addition, transplantation of UMSCs reduced the permeability of the intestine and also increased the expression of tight junction proteins, which help knit the colonic cells together and maintain the structural integrity of the colon. These results show that the anti-inflammatory properties of UMSCs and their capacity to regulate tight junction proteins ameliorates ulcerative colitis.
A new Phase I clinical trial has demonstrated that Multiple Sclerosis (MS) patients were able to safely tolerate treatment with cells cultured from human placental tissue. The results of this study were recently published in the journal Multiple Sclerosis and Related Disorders. This pioneering study was conducted by researchers at Mount Sinai, Celgene Cellular Therapeutics, which is a subsidiary of Celgene Corporation, and collaborators at several other institutions, including the Swedish Neuroscience Institute in Seattle, WA, MultiCare Health System-Neuroscience Center of Washington, London Health Sciences Centre at University Hospital in London, the Clinical Neuroscience Research Unit at the University of Minnesota, the University of Colorado Denver, The Ottawa Hospital Multiple Sclerosis Clinic, and the MS Comprehensive Care Center at SUNY.
Even though this clinical trial was designed solely to determine the safety of this treatment, the data collected from the participating patients suggested that a preparation of cultured cells called PDA-001 may repair damaged nerve tissues in patients with MS. PDA-001 cells resemble “mesenchymal,” stromal stem cells, which are found in many tissues of the body. However, in this study, the cells were grown in cell culture systems, which means that one donor was able to supply enough cells for several patients.
“This is the first time placenta-derived cells have been tested as a possible therapy for multiple sclerosis,” said Fred Lublin, MD, Director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Professor of Neurology at Icahn School of Medicine at Mount Sinai and the lead investigator of the study. “The next step will be to study larger numbers of MS patients to assess efficacy of the cells, but we could be looking at a new frontier in treatment for the disease.”
MS is a chronic autoimmune disease. The body’s immune system attacks the insulating myelin sheath that surrounds and protectively coats the nerve fibers in the central nervous system. The myelin sheath greatly improves the speed at which nerve impulses pass through these nerves and without the myelin sheath, nerve impulse conduction becomes sluggish, and the nerves also eventually die off. Long-term, MS causes extensive nerve malfunction and can lead to paralysis and blindness. MS usually begins as an episodic condition called “relapsing-remitting MS” or RRMS. Patients will have occasional outbreaks of nerve malfunction, pain, or numbness. However, many MS patients will see their condition evolves into a chronic condition with worsening disability called “secondary progressive MS” or SPMS.
This Phase I trial examined 16 MS patients, 10 of whom had RRMS and six of whom were diagnosed with SPMS and were between the ages of 18 and 65. Six patients were given a high dose of the placental-based cell line PDA-001, and another six were given a lower dose. The remaining four patients were given placebos. Dr. Lubin noted that alteration of the immune system by any means can cause MS to worsen in some patients. Therefore, all participating subjects were given monthly brain scans over a six-month period to ensure they did not acquire any new or enlarging brain lesions, which are indicative of worsening MS activity. However, none of the subjects in this study showed any paradoxical worsening on MRI and after one year. The majority had stable or improved levels of disability.
“We’re hoping to learn more about how placental stromal cells contribute to myelin repair,” said Dr. Lublin. “We suspect they either convert to a myelin making cell, or they enhance the environment of the area where the damage is to allow for natural repair. Our long-term goal is to develop strategies to facilitate repair of the damaged nervous system.”
Autoimmune diseases are those diseases in which the patient’s own immune system attacks his or her own tissues. the treatment of such diseases requires giving patients drugs that suppress the immune system. Such drugs have potent side effects and taking such drugs long-term can also predispose patients to cancers and other types of inimical conditions.
One particular type of autoimmune disease, Systemic Lupus Erythematosis, otherwise known as SLE or just Lupus, results from an immune response against components inside our cells. The recognition of these proteins and other substances by our immune system causes massive cell damage and death. However, lupus is a very individual disease. In some patients, the disease manifests by producing butterfly-like lesions on the face.
In others, a severe arthritis in several joints results. In other lupus patients, the liver undergoes progressive degradation and scarring. Still others have severe heart problems, and others have scarring and progressive damage to the kidneys. In other patients a combination of symptoms and organs are affected. Some cases of lupus are sporadic and mild, but others are fulminant and relentless. The particular disease a person shows is completely individual.
In some lupus patients, the kidneys experience lupus nephritis (LN), which is inflammation of the tissues of the kidney. In some patients, drug treatments with corticosteroid drugs like prednisone, or other drugs like hydroxychloroquine (Plaquenil), also can help control lupus. Other drugs include powerful immune suppressants such as cyclophosphamide (Cytoxan), azathioprine (Imuran, Azasan), mycophenolate (Cellcept), leflunomide (Arava) and methotrexate (Trexall), all of which have lists of side effects that include increased risk of infection, liver damage, decreased fertility and an increased risk of cancer. However in a percentage of LN patients, drug treatments simply do not work, and these conditions are known as refractory LN.
A new clinical trial has examined the ability of mesenchymal stem cells from bone marrow or umbilical cord tissue to treat refractory LN. This Chinese study examined 81 patients with active refractory LN. The mesenchymal stem cells (MSCs) used in this study were “allogeneic,” which means that they were taken from someone other than the patient. Such treatments have been shown to successfully treat patients with other types of autoimmune diseases (see Figueroa FE, et al., Biol Res. 2012;45(3):269-77).
In this single-center clinical trial, Fei Gu and Dandan Wang and others from the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China enrolled 81 Chinese patients with active and refractory LN from 2007 to 2010. These patients received by intravenous administration either allogeneic bone marrow- or umbilical cord-derived MSCs at a dose of 1 million cells per kilogram of bodyweight. All 81 patients were then monitored over the course of one year with periodic follow-up visits to evaluate kidney function and to determine if the patients were experiencing any adverse events from the stem cell treatments.
During the year-long follow-up, 77 of the 81 patients survived ( survival rate of 95%) and 49/81 patients (60.5%) achieved remission. Eleven of 49 (22.4 %) patients showed a “renal flare,” which means that their symptoms and kidney inflammation returned by the end of 12 months after having previously experienced complete remission.
Kidney function jumped during this time. The main measure of kidney function is a test called the glomerular filtration rate or GFR. This measures how well the kidney filters materials per unit time. GFR in these patients improved significantly 12 months after the stem cell treatment (mean ± SD, from 58.55 ± 19.16 to 69.51 ± 27.93 mL/min). Two other measures used to determine the severity of lupus in a patient (Systemic Lupus Erythematosus Disease Activity Index or SLEDAI score), and the activity of lupus within the kidney (British Isles Lupus Assessment Group or BILAG scores) also decreased consistently, showing that the severity of the disease decreased and the severity of the disease within the kidney also decreased after the stem cell treatment (BILAG scores – 4.48 ± 2.60 at baseline to 1.09 ± 0.83 at 12 month and the SLEDAI scores – 13.11 ± 4.20 at baseline to 5.48 ± 2.77 at 12 months).
If that is not convincing, get this: the doses of prednisone and immunosuppressive drugs required by these patients were tapered. In other words, patients were able to eventually get off their drugs sometime within this year-long period. Is that cool or what!! No transplantation-related adverse events were observed.
Thus, the authors conclude, “Allogeneic MSCT resulted in renal remission for active LN patients within 12-month visit, confirming its use as a potential therapy for refractory LN.”
Now this treatment is NOT a cure. Several patients still experienced renal flares one year after treatment, and not all the patients experienced remission. Therefore, this is not a treatment for everyone. Identifying which patients will be helped by these treatments might require microarray analyses, but the bottom line is clear – some patients are definitely helped by MSC treatments.
Granted this is a small study and it is not a controlled study – these stem cell-treated patients were not compared to anything else. However it is a very hopeful beginning. There were no adverse side effects and 60% of the patients experienced remission, and that is definitely good news
Chinese physicians and stem cell researchers from Shenzhen, China have reported on their clinical trial that treated 40 patients with severe and refractory lupus systemic erythematosus with mesenchymal stem cells isolated from umbilical cord. This 40-patient, multicenter study targeted patients with active and difficult-to-treat lupus.
Systemic lupus erythematosus (SLE), which is also simply known as lupus, is an autoimmune disease in which the body’s immune system mistakenly attacks healthy tissue. Lupus can affect the skin, joints, kidneys, brain, or even other organs.
What causes lupus is uncertain, but tissue damage seems to predispose some people to the onset of lupus. Lupus commonly affects women than men, and it can occur at any age. It most commonly appears most often in people between the ages of 10 and 50, and African-Americans and Asians are affected more often than people from other ethnic groups. Particular drugs have also been linked to the onset of lupus or lupus-like conditions (e.g., isoniazid, hydralazine, procainamide, and less commonly anti-seizure medicines, capoten, chlorpromazine, etanercept, infliximab, methyldopa, minocycline, penacillamine, quinidine, and sulfasalazine).
The symptoms of lupus vary tremendously and they usually come and go. Almost all lupus patients have some joint pain and swelling, and some develop arthritis. Typically the joints of the fingers, hands, wrists, and knees are most often affected. Other symptoms include chest pain when taking a deep breath, fatigue, fever, general discomfort, uneasiness, or ill feeling (malaise), hair loss, mouth sores, swollen lymph nodes, and sensitivity to sunlight. Also, a specific type of skin rash known as a “butterfly” rash occurs in about half of lupus patients. The butterfly rash is most often seen over the cheeks and bridge of the nose, but can be widespread and gets worse in sunlight. Some people have only skin symptoms and have what is known as discoid lupus.
Chronic lupus usually becomes concentrated in specific organs, which can cause secondary symptoms. These symptoms can include:
Thus more efficacious and safe ways to treat recalcitrant cases of lupus have included stem cell treatments. In particular, mesenchymal stem cells and their ability to suppress inflammation. To that end, several pre-clinical and clinical trials have tested mesenchymal stem cells from bone marrow, fat and umbilical cord to reduce the chronic inflammation associated with particular autoimmune diseases (see P Connick, et al., Lancet Neurol. 2012 Feb;11(2):150-6; MM Bonab, et al., Curr Stem Cell Res Ther. 2012 Nov;7(6):407-14; J Voswinkel, et al., Immunol Res. 2013 Jul;56(2-3):241-8; P Connick P, et al., Trials. 2011 Mar 2;12:62; D Karussis, et al., Arch Neurol. 2010 Oct;67(10):1187-94; B Yamout, et al., J Neuroimmunol. 2010 Oct 8;227(1-2):185-9).
This new Chinese trial provides some very interesting and welcome data on the use of mesenchymal stem cells from umbilical cord to treat lupus.
Dr. Xiang Hu, who founded the biotechnology company Beike, said, “We are pleased with the results we have seen in our clinical trial. While some severe cases experienced relapse after 6 months, the results show a markedly improved quality of life expectation. This is a big step forward in combating autoimmune disease. We will now be looking to further our SLE research efforts to find even better results.”
The forty patients who participated in the study were recruited from four centers in China. The umbilical cord-derived mesenchymal stem cells used in the study were processed by Beike Biotech’s scientists at the company’s new state-of-the-art Jiangsu Stem Cell Regenerative Medicine Facility in Taizhou, China. Stem cells from sources other than the patient’s own body are known as allogeneic stem cells, and these forty patients, all of whom have refractory lupus were infused with umbilical cord mesenchymal stem cells intravenously at the beginning of the study and one week later. To score each patient’s disease progression, a clinical test called a SLEDAI or Systemic Lupus Erythematosus Disease Activity score. The SLEDAI score results from a compilation of multiple clinical and laboratory tests.
After 6 months, all patients showed significant improvement in their SLEDAI scores, but after six months, several patients experienced relapse, which required a repeat treatment with mesenchymal stem cells. Also, the safety profile of these cells was superior to many of the drugs used to treat lupus.
This study is suggests that the mesenchymal stem cells suppress active lupus without causing severe adverse effects. However, in order to show that definitively, a double-blinded, placebo-controlled study must be conducted. Also, trying to provide longer periods of relief rather than just six months of relief is another factor that further work will hopefully address.
A collaborative study between physicians at the Hospital of Chinese People’s Liberation Army and the University of Oklahoma Health Sciences Center has examined the efficacy of umbilical cord mesenchymal stem cell treatments in combination with drugs in patients with active rheumatoid arthritis (RA).
RA may exist in 0.5-1.0% of the general population. In 2005, an estimated 1.5 million US adults aged ≥ 18 (0.6%) had RA. RA is characterized by chronic inflammation of the joints that causes cartilage and bone damage and deformity. It occurs in women two to three times more often than men.
Treatment of RA requires the administration of disease-modifying antirheumatic drugs (DMARDs), Unfortunately, these drugs have sizable side effects, and less debilitating treatments would be a welcome addition to the treatment options for RA patients.
A paper by Liming Wang and colleagues that was published in Stem Cells and Development examines the efficacy of combining DMARDs with infusions of umbilical cord mesenchymal stem cells (MSCs). Since MSCs have the ability to suppress an overactive immune response, such treatments might provide relief from the symptoms of RA and decrease the dependence on DMARDs.
In this study, Wang and others enrolled 172 RA patients and divided them into two groups: 36 of them were treated with DMARDs alone and 136 were treated with DMARDs plus umbilical cord MSCs (UC-MSCs). Of these 136 patients, 76 were treated for 3 months, 45 for 6 months, and 15 for 8 months. Each of these groups consisted of patients who could and who could not tolerate DMARDs. All patients in the second group received 4 x 10 UC-MSCs in 40 milliliters of liquid, but the first group received stem cell “solvent” (whatever that is) without UC-MSCs.
The results clearly showed that UC-MSCs treatments are safe. Patients blood work-ups before and after treatment show no significant differences. Secondly, the DMARD-only group did not show any improvements, but they did not get worse either. The DMARD + UC-MSC group showed quantifiable improvements. These patients reported feeling better in health assessment questionnaires, their serum levels of C-reactive protein and rheumatoid factor went down and their numbers of regulatory T-cells went up. The joint evaluations of these patients also improved (the so-called DAS28 score). All of these are measures of the severity of RA, and in the DMARD + UC-MSC groups, all the these markers improved.
Other markers of RA severity such as IL-6 and TNF-alpha also decreased in the DMARD + UC-MSC patients.
From these data, Wang and others conclude that “UC-MSCs are suitable pllications in the clinic and provide an additional choice to many RA patients.”
The data in this paper are rather clear. The benefits of a single UC-MSC treatment are significant. For this reason, umbilical cord MSCs should be regarded as a potential adjuvant treatment for RA patients.
Medical researchesr from UC San Francisco have used embryonic stem cells to construct a functioning mouse thymus in the laboratory. When implanted into a living mouse, this laboratory-made thymus can successfully foster the development of T cells, which the body needs to fight infections and prevent autoimmune reactions.
This achievement marks a significant step toward developing new treatments for autoimmune disorders such as type 1 diabetes and other autoimmune diseases, such as systemic lupus erythematosis and ulcerative colitis.
This research team was led by immunologist Mark Anderson and stem cell researcher Matthias Hebrok. They used a unique combination of growth factors to push the embryonic stem cells into a particular developmental trajectory. After a period of trial and error, they eventually found a formula that produced functional thymus tissue.
In our bodies, the thymus lies just over the top of our heart, and it serves to instruct T lymphocytes (a type of white blood cell) what to attack and what to leave alone. Because T cells serve a vital role in the immune response, the thymus serves a vital function.
Typically, each T cell attacks a foreign substance that it identifies by binding the foreign substance to its cell surface receptor. This T cell-specific receptor is made in each T cell by a set of genes that are randomly shuffled, and therefore, each T cell has a unique cell receptor that can bind particular foreign molecules. Thus each T cell recognizes and attacks a different foreign substance.
With in the thymus, T cells that attack the body’s own proteins are eliminated. Thymic cells express major proteins from elsewhere in the body. The T cells that enter the thymus first undergo “Positive Selection” in which the T cell comes in contact with self-expressed proteins that are found in almost every cell of the body and are used to tell “you” from something that is not from “you.” In order to destroy cells that do not bear these self-expressed proteins, they must be able to properly identify them. If T cells that enter the thymus cannot properly recognize those self-expressed proteins (known as MHC or major histocompatibility complex proteins for those who are interested), the thymus destroys them. Second, T cells undergo “Negative Selection” in which if the T cell receptor binds to self MHC proteins, that T cell is destroyed to avoid autoimmunity.
The thymus tissue grown in the laboratory in this experiment was able to nurture the growth and development of T cells. It could act as a model system to study patients with fatal diseases from which there are no effective treatments, according the Mark Anderson.
As an example, DiGeorge Syndrome is caused by a small deletion of a small portion of chromosome 22 and infants born with DiGeorge Syndrome are born without a thymus and they usually die during infancy.
Other applications include manipulating the immune system to accept transplanted tissues such as implanted stem cells or organs from donors that are not a match to the recipient.
Anderson said, “The thymus is an environment in which T cells mature and where they also are instructed on the difference between self and nonself.” Some T cells are prepared by the thymus to attack foreign invaders and that includes transplanted tissue. Other T cells that would potentially attack our own tissues are eliminated by the thymus.
Laboratory-induced thymus tissue could be used to retrain the immune system in autoimmune diseases so that the T cells responsible for the autoimmune response eventually ignore the native tissues they are attacking.
Hebrok warns that he and his team have not perfectly replicated a thymus. Only about 15% of the cells are successfully directed to become thymus tissue with the protocols used in this study. Nevertheless, Anderson asserted, “We now have developed a tool that allows us to modulate the immune system in a manner that we never had before.”
In the journal Stem Cells and Development, there is a case report from the University Hospital at Karolinska Institutet in Stockholm, Sweden of a 21-year-old man who suffered from a rare immune disorder and was treated with an infusion of mesenchymal stem cells (MSCs) from a donor.
This patient was seen in October, 2010 and had been suffering from a fever for 2 months. He had had a previous gastrointestinal infection that had resolved, but the inflammation that resulted from the infection refused to go away. He was diagnosed with hemophagic lymphohistiocytosis (HLH). This is a mouthful, but it is a relatively rare immune disorder that results in pronounced systemic hyperinflammation. This hyperinflammation essentially results from some sort of infection that causes inflammation, but the inflammation does not turn off when the infection resolves. The condition causes the spleen to enlarge and the number of blood cells to decrease to abnormally low levels and the patient has a constant, burning fever.
The medical team that treated this poor soul used steroids, and that worked from about a week. Then they tried the HLH-94 treatment protocol, which involves treating the patient with a combination of powerful immunosuppressive drugs; etoposide, (VP-16), corticosteroids, CyclosporinA, and, in some patients, intrathecal methotrexate, before the patient is given a bone marrow transplant. The HLH-94 protocol returned the patient to normal – for about 2 months, and then the patient was back to square one.
At this point, the medical team needed a Hail Mary, if you will. Therefore, they decided to use MSCs from a healthy donor. The patient was given a total of 124 million bone marrow-derived MSCs, and within 24 hours, the patient’s fever was gone and his blood work normalized.
Unfortunately, the poor chap contracted a nasty fungal infection that, in his weakened state, spread throughout his whole body and killed him. However, postmortem examinations showed that the MSCs had mobilized a whole gaggle of special white blood cells called macrophages, and these MSC-recruited macrophages suppressed the over-active immune response of this HLH patient. The fungal infection was contracted before the administration of the MSCs, therefore, the stem cell treatment had no causal relationship to the fungal infection.
However, this case study suggests that MSCs have a future in the treatment of immune disorders. Furthermore, the use of MSCs from donors can also provide therapeutic material for the treatment of immune disorders.
A detailed review article in the June issue of Plastic and Reconstructive Surgery, the official medical journal of the American Society of Plastic Surgeons, has examined the safety and clinical efficacy of fat-derived stem cells. Stem cells from fat, also known as ACSs, are a promising source of cells for use in plastic surgery and regenerative medicine, according to this review, but there are still many questions that remain about them. Much more research is needed in order to completely establish the safety and effectiveness of ASC-based therapies in human patients. The review article was written by ASPS Member Surgeon Rod Rohrich, MD of University of Texas Southwestern Medical Center, Dallas, and his colleagues (Dr. Rohrich is Editor-in-Chief of Plastic and Reconstructive Surgery).
ASCs are very easily procured from humans, since simple procedures such as liposuction can provide more than enough material for therapies. On the average, one gram of fat yields about 5,000 stem cells, whereas the yield from the same quantity of bone marrow is about 1,000 cells (B. M. Strem, K. C. Hicok, M. Zhu et al., “Multipotential differentiation of adipose tissue-derived stem cells,” Keio Journal of Medicine, vol. 54, no. 3, pp. 132–141, 2005.). Once isolated from the fat, ASCs have the capacity to form fat cells, but also bone, cartilage and muscle cells.
From a therapeutic standpoint, ASCs promote the development of new blood vessels (angiogenesis). ASCs are also not recognized by the immune system and they seem to staunch inflammation. According the Dr. Rohrich and is co-authors, “Clinicians and patients have high expectations that ASCs may well be the answer to curing many recalcitrant diseases or to reconstruct anatomical defects.”
Fortunately, there is great interest in ASCs, and this means that the number of studies that examine ASCs or utilize them for experimental treatments have soared. Unfortunately, there is continued concern about the “true clinical potential” of ASCs. In the words of this new article, “For example, there are questions related to isolation and purification of ASCs, their effect on tumor growth, and the enforcement of FDA regulations.”
Rohrich and others conducted a rather in-depth review of all known clinical trials of ASCs. Thus far, most studies have been performed in Europe and Korea, and only three in the United States, to date. This reflects the stringency of FDA regulations.
Most ASC clinical trials to date have been examined the use of ASCs in plastic surgery. In this case, plastic surgeon-researchers have used ASCs for several types of soft tissue augmentation (breast augmentation, especially after implant removal and regeneration of fat in patients with abnormal fat loss or lipodystrophy). Studies exploring the use of ASCs to promote healing of difficult wounds have been reported as well. ASCs have also been used as in so-called soft tissue engineering or tissue regeneration. In these cases, the results have been inconclusive.
Other medical specialties have also made use of ASCs as treatments for other types of medical conditions. For example, ASCs have been studied for used to treat certain blood and immunologic disorders, heart and vascular problems, and fistulas (abnormal connection between an organ, vessel, or intestine and another structure). There are some other studies that have examined the use of ASCs for generating new bone for use in reconstructive surgery. A few studies have reported promising preliminary results in the treatment of diabetes, multiple sclerosis, and spinal cord injury. Perhaps one of the most encouraging results was the complete absence of serious adverse events related to ASCs in any of these studies.
These results are encouraging, but all of these applications are in their infancy. Globally speaking, less than 300 patients have been treated with ASCs, and no standardized protocol exists for the preparation or clinical applications of ASCs. Additionally, there is no consensus as to the number of ASCs required per treatment, or how many treatments are required for the patient to show clinical improvement. Thus Rohrich and his colleagues have taken a “proceed with caution approach.” They conclude that “further basic science experimental studies with standardized protocols and larger randomized controlled trials need to be performed to ensure safety and efficacy of ASCs in accordance with FDA guidelines.”
Multiple sclerosis is a disease that results when the immune system attacks the myelin insulation that wraps and covers particular nerves. It is, therefore, part of a larger group of diseases called “autoimmune diseases.” Because multiple sclerosis involves nerves, it affects the brain, spinal cord, and some peripheral nerve as well.
Typically, multiple sclerosis (MS) affects women more than men, which is common for most autoimmune diseases. It is most commonly diagnosed between ages 20 and 40, but can it show up in anyone at practically any age. The main cause of the pathology of multiple sclerosis is immune system-mediated damage to the protective covering that surrounds some, though not all nerves, the myelin sheath. Myelin sheaths help nerves transmit their nerve impulses faster, and without it, nerve signals slow down or stop altogether.
Damage to the myelin sheath results from specific immune cells that recognize the myelin sheath as a foreign invader. The attacks against the myelin sheath cause inflammation at the nerves. Inflammation results from immune cell activities whereby activated immune cells secrete chemicals called “cytokines” that sound the alarm in the immune system. These cytokines recruit other immune cells to the site of injury or infection and the cells make antibodies against the foreign substance and other cells gobble up the foreign substance and destroy it. You can see why the nerves take such a beating during multiple sclerosis.
Why does this happen in the first place? There is no clear answer to this question. Clearly some people are more prone than others to develop multiple sclerosis. Infection of the nerves by particular viruses that cause the immune system to recognize it as foreign is another possibility, and other blame environmental factors.
Over half the patients with multiple sclerosis have progressive disease characterized by accumulating disability, and there are no treatments for them. Several experiments have established the ability of mesenchymal stem cells to suppress the damaging effects of autoimmune disorders, and in acute and chronic animal models of multiple sclerosis mesenchymal stem cells have many beneficial effects. A recent paper has reported attempts to determine the safety and efficacy of mesenchymal stem cells as a potential treatment for secondary progressive multiple sclerosis. The paper is Connick, P., et al., “Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study,” Lancet Neurology 11(2): 2012:159-6. Paper
For this research, Connick and his colleagues recruited people from East Anglia and north London that suffered from secondary progressive multiple sclerosis that affects the visual pathway. Because the ability to see is relatively easy to determine with eye tests, this population was a prime set of candidates for this study. Study subjects received intravenous infusions of their own bone-marrow-derived mesenchymal stem cells. Safety and feasibility were two of the factors that were examined in this study.
Side effects were examined from 20 months before treatment until up to 10 months after the infusion. Also, the eyesight of the patients was ascertained by eye tests, but the nerves were directly tested for their ability to send nerve impulses. Multiple sclerosis prevents nerves from being able to form and propagate proper nerve impulses, and if this treatment works, then it should improve the ability of the nerves to form nerve impulses.
In ten patients, no serious side effects were observed (rashes after the injection and so on). However, an improvement in visual acuity was observed in almost all the patients. The field of vision increased, as did the ability of the nerves to form nerve impulses. Color vision and the structure of the retina were no affected, but the increase in vision was significant.
Thus, autologous mesenchymal stem cells were safely administered to patients with secondary progressive multiple sclerosis, and there is even some evidence of structural, functional, and physiological improvement after treatment. These data suggest that mesenchymal stem cells possibly modulate the immune response in these patients and protect the nerves. While these results are preliminary, they certainly warrant further investigation.
Recent findings published in the Journal of Translational Medicine report the first ever treatment of autoimmune diseases with fat-derived stem cells. The article is entitled “Stem cell treatment for patients with autoimmune disease by systemic infusion of culture-expanded autologous adipose tissue derived mesenchymal stem cells,” and contained contributions from researchers in five different countries: South Korea, United States, Japan, China, and Germany.
The senior author, Jeong Chan Ra, president of RNL Stem Cell Technology Institute, and his collaborators were successful in treating patients with autoimmune diseases who had experienced severe tissue damage as a result of their diseases and had limited treatment options.
Autoimmune diseases are caused by mis-regulation of the immune system that allows the body’s immune system to attack the very tissues and organs that house it. There are different kinds of autoimmune diseases which include systemic lupus erythematosis, rheumatoid arthritis, multiple sclerosis, autoimmune hearing loss, spastic myelitis, Bechet’s syndrome and so on. Symptoms of autoimmune diseases are long-term, and these diseases often caused permanent damage.
In previous work, Ra’s team demonstrated the safety of intravenously infused adipose (fat)-derived stem cells in humans. Patients who received multiple stem cell infusions showed no adverse effects and no severe side effects. In this present study, the team showed that infusions of these stem cells were effective in treating diseases that ranged from autoimmune hearing loss, multiple sclerosis, polymyositis, atopic dermatitis, and rheumatoid arthritis, in this study.
In the case of autoimmune hearing loss, the patient was administered with her own stem cells. Her hearing returned to normal (scaled out to 15 decibels) even though she had previously not responded to steroid treatments.
A multiple sclerosis patient suffered severe side effects from high dose steroid treatments and had difficulty walking. However after infusions of her own stem cells, her condition improved tremendously, and she was able to move her legs using her own muscular strength.
Other autoimmune diseases treated in this paper were patients with multiple sclerosis, atopic dermatitis, and rheumatoid arthritis, all of whom were not able to be treated with existing medication. However, after multiple infusions of their own fat-derived stem cells, their illnesses became manageable.
Researchers are continuing to develop sophisticated stem cell technology using five grams of fat as a standard, which can be expanded to 1 billion stem cells. This technology became more efficient and convenient for patients because repetitive stem cell injections are possible from one time fat extraction. These studies also showed that the fat-derived stem cells were capable of homing to the site of damage where they were able to suppress the inflammation that was the cause of the pathology and symptoms of these diseases. These patients required less surgeries, transplants and fewer drugs.
Dr. Ra said: “The fact that we showed the way patients can be treated from their own stem cells is very rewarding to me. We are working towards becoming our country’s medical hub for treating autoimmune diseases.”