Yang et al. Clin Toxicol (Phila). 2011 Apr;49(4):298-302.
Paraquat is a herbicide that is linked to development of Parkinsons. It also is a toxin to lung cells and is used as a model of inducing lung injury in rats. In the current study the investigators wanted to see if administration of bone marrow mesenchymal stem cells had a therapeutic effect on paraquat-induced lung injury in rats.
The investigators used 54 female SD rats that were randomly divided into four groups:
a) Paraquat treated group,
b) Paraquat and bone marrow mesenchymal stem cell treated group,
c) Bone marrow mesenchymal stem cell alone treated group
d) Control untreated group
The stem cells were injected intravenously and animals were sacrificed 14 days after injection.
While animals receiving paraquat alone lived an averaty of 9.6 days, all rats receiving bone marrow mesenchymal stem cells lived more than 14 days. Bone marrow mesenchymal stem cell treatment was associated with less wet lung, decreases in plasma IL-1 and TNF-alpha, decrease in MDA, and decrease in NF-kappa B. Upregulated levels of the antioxidant enzyme superoxide dismutase was observed.
The ability to stimulate repair of the lung by mesenchymal stem cells is not new. Previous studies have shown that mesenchymal stem cells are capable of reducing endotoxin induced lung injury by secretion of keratinocyte growth factor. Other studies have shown that mesenchymal stem cells produce interleukin 1 receptor antagonist in the bleomycine induced model of lung fibrosis.
As with other stem cell therapies described on this website, there is some controversy as to the biological mechanisms by which the stem cells are mediating their therapeutic effect. One possibility is that they are secreting growth factors that stimulate proliferation of endogenous stem cells that are already resident in the lung. The other possibility is that the stem cells are directly differentiating into lung tissue.
Bone Marrow Stem Cells Protect Lungs from Herbicide Injury
Stem Cell trial volunteers thank doctors at reunion lunch
Miami Herald, by Fred Tasker, ftasker@MiamiHerald.com
Stem cell therapy was originally used for the treatment of leukemias in the form of bone marrow transplant. Nearly 2 decades after this groundbreaking work, clinical trials initiated using bone marrow stem cells for treatment of heart patients. Bone marrow stem cells possess the ability to stimulate new blood vessel formation, a process called angiogenesis, which is essential in: a) accelerating healing after a heart attack; and b) in patients who have angina, stimulating new blood vessels to grow and take over the function of the clogged arteries that are causing the angina.
Initial work in this area involved administering stem cells from the bone marrow that were non-purified, directly into the heart muscle. Subsequently new techniques were developed so that open heart surgery was not needed. These techniques include the use of catheter-based delivery systems. Additionally, scientists found that one type of stem cell that is found in the bone marrow, called the mesenchymal stem cells, is actually more potent than bone marrow non-purified cells. Clinical trials have been performed with mesenchymal stem cells for heart failure. One of the major ones involved intravenous administration of “universal donor” cells. This article describes some of the patients that participated in Osiris’ 51 patient clinical trial.
“I believe in miracles, God — and my doctors,” said Edgar Irastorza, 33, the youngest of 51 patients at the luncheon.
Early results are promising, says Hare, director of UM’s Interdisciplinary Stem Cell Institute.
“We don’t know what the results will be, but things are going well. The fact that you’re here is testament to that,” he told the patients, united for the first time at a luncheon titled “Heart of a Pioneer” to celebrate their struggle.
Irastorza, a Miami property manager, said he died briefly on Oct. 6, 2008. A genetic defect gave him such a serious heart attack that his heart stopped for a few minutes. Doctors who revived him said half his heart was dead and warned him to prepare for a short, disabled life. They wanted to insert a defibrillator into his chest.
“I didn’t want that,” he said. “I didn’t want to give up sex and dancing.”
On March 3, 2010, UM doctors used a catheter inserted through a slit in his groin to inject millions of tiny stem cells into his damaged heart.
At the Friday luncheon, Irastorza presented to the crowd a five-minute video of his new self, doing an energetic, head-spinning break dance.
“I’m not completely back to normal, but, compared to before, it’s night and day,” he said.
Felix Morales, 80, a retired agriculture worker, had a heart attack 25 years ago and recently had become too easily fatigued to take care of the collards and peppers and the mamey and mango trees in his Miami backyard.
A year ago, he got one of the stem-cell treatments. “It took a while, but I feel good right now,” he said. “I have no words to express my gratitude.”
Evangeline Gordon, 40, a state probation officer from Miami, called 911 one October night in 2009, thinking she had a bad gas attack. To her shock, doctors told her a heart attack had damaged 70 percent of her heart muscle. They began discussing a heart transplant.
Instead, she volunteered for the UM program and got stem cells from a donor. Like most of the others, she doesn’t know if she got real stem cells or a placebo treatment used for comparison.
“I’m up and down,” she said Friday. “I still get angina and fatigue, but I don’t feel like I’m going down anymore.”
Forcing Stem Cells into Circulation Results in Protection from Liver Failure in Animals
Zhang et al. Toxicol Lett.
While previous studies showed that administration of bone marrow cells are capable of repairing livers in animal and human studies, relatively little work has been performed to augment existing means by which the body uses its own stem cells to heal the liver. Specifically, it has been demonstrated that in liver failure bone marrow stem cells exit the bone marrow and home to the damaged liver. While conventional approaches include performing a bone marrow aspiration and mechanically placing the bone marrow into the liver, usually vial the hepatic artery, an alternative would be administration of a chemical that “instructs” the bone marrow stem cells to exit the bone marrow and go into systemic circulation. The other approach would be to augment the chemical signals that the injured liver produces to attract stem cells. This approach is currently pursued in other indications by the company Juventas. Stromal Derived Factor (SDF)-1 is produced by injured tissues and induces migration of bone marrow stem cells. The genetic administration of SDF-1 into already injured tissues causes an increase in stem cell trafficking and has been demonstrated to augment existing regenerative mechanisms.
A recent study (Zhang et al. Granulocyte colony-stimulating factor treatment ameliorates liver injury and improves survival in rats with d-galactosamine-induced acute liver failure. Toxicol Lett. 2011 Apr 27) from the First Affiliated Hospital, School of Medicine, of the Xi’an Jiaotong University demonstrated that administration of the stem cell mobilizer G-CSF into rats with chemically induced liver failure results in prolonged survival and the appearance of liver regeneration.
The investigators administered a single dose of d-galactosamine (d-GalN, 1.4g/kg) to induce ALF. After 2h, the rats were randomized to receive G-CSF (50μg/kg/day), or saline vehicle injection for 5 days. In the liver failure model, 5-day survival after d-GalN injection was 33.3% (10/30), while G-CSF administration following d-GalN resulted in 53.3% (16/30) survival (p=0.027). G-CSF treated rats had lower ALT level and less hepatic injury compared with saline vehicle rats. The increases of CD34+ cells in bone marrow and liver tissue and Ki-67+ cells in liver tissue in G-CSF treated rats were higher than those in saline rats.
These data suggest the possibility that stem cell therapy using chemicals that mobilize endogenous stem cells may be useful in the treatment of liver failure. It remains to be seen whether other chemicals associated with mobilization may cause improved outcome. For example, in addition to G-CSF, agents such as M-CSF, GM-CSF, parathyroid hormone, and the CXCR4 antagonist Mozibile are all capable of inducing mobilization of different types of stem cells.
Immune Cells Killing Stem Cells and Stem Cells Killing Immune Cells
Knight et al. J Neurol Sci.
Several studies have demonstrated that stem cells are useful in the treatment of multiple sclerosis. The Cellmedicine clinic published previously in collaboration with the University of California San Diego that 3 patients treated with their own fat derived stem cells entered remission. Other studies are ongoing, including a study at the Cleveland Clinic in which bone marrow stem cells differentiated into mesenchymal stem cells are being administered into patients with multiple sclerosis. Unfortunately the mechanisms by which therapeutic effects occur are still largely unknown. One general school of thought believes that stem cells are capable of differentiating into damaged brain cells. The other school of thought believes that stem cells are capable of producing numerous growth factors, called trophic factors, that mediate therapeutic activity of the stem cells. Yet another school of thought propagates the notion that stem cells are merely immune modulatory cells. Before continuing, it is important to point out that stem cell therapy for multiple sclerosis involving autologous hematopoietic transplants is different than what we are discussing here. Autologous (your own) hematopoietic stem cell therapy is not based on regenerating new tissues, but to achieve the objective of extracting cells from a patients, purifying blood making (hematopoietic) stem cells, destroying the immune system of the recipient so as to wipe out the multiple sclerosis causing T cells, and subsequently readministering the patient’s own cells in order to regenerate the immune system. This approach, which was made popular by Dr. Richard Burt from Northwestern University.
In order to assess mechanisms of how stem cells work in multiple sclerosis it is necessary to induce the disease in animals. The most widely used animal model of multiple sclerosis is the experimental allergic encephalomyelitis model. This disease is induced in female mice that are genetically bred to have a predisposition to autoimmunity. These animals are immunized with myelin basic protein or myelin oligodendrocyte protein. Both of these proteins are components of the myelin sheath that protects the axons. In multiple sclerosis immune attack occurs against components of the myelin sheath. Therefore immunizing predisposed animals to components of the myelin sheath induces a disease similar to multiple sclerosis. The EAE model has been critical in development of some of the currently used treatments for multiple sclerosis such as copaxone and interferon.
Original studies have demonstrated that administration of bone marrow derived mesenchymal stem cells protects mice from development of EAE. This protection was associated with regeneration on oligodendrocytes as well as shifts in immune response. Unfortunately these studies did not decipher whether the protective effects of the stem cells were mediated by immune modulation, regeneration, or a combination of both. Other studies have shown that MSC derived from adipose tissue had a similar effect. One interesting point of these studies was that the stem cell source used was of human origin and the recipient mice were immune competent. One would imagine that administration of human cells into a mouse would result in rapid rejection. This did not appear to be the case since the human cells were found to persist and also to differentiated into human neural tissues in the mouse. One mechanism for this “immune privilege” of MSC is believed to be their low expression of immune stimulatory molecules such as HLA antigens, costimulatory molecules (CD80/86) and cytokines capable of stimulating inflammatory responses such as IL-12. Besides not being seen by the immune system, it appears that MSC are involved in actively suppressing the immune system. In one study MSC were demonstrated to naturally home into lymph nodes subsequent to intravenous administration and “reprogram” T cells so as to suppress delayed type hypersensitive reactions. In those experiments scientists found that the mechanism of MSC-mediated immune inhibition was via secretion of nitric oxide. Other molecules that MSC use to suppress the immune system include soluble HLA-G, Leukemia Inhibitor Factor (LIF), IL-10, interleukin-1 receptor antagonist, and TGF-beta. MSC also indirectly suppress the immune system by secreting VEGF which blocks dendritic cell maturation and thus prevents activation of mature T cells.
While a lot of work has been performed investigating how MSC suppress the immune system, relatively little is known regarding if other types of stem cells, or immature cells, inhibit the immune system. This is very relevant because there are companies such as Stem Cells Inc that are using fetally-derived progenitor cells therapeutically in a universal donor fashion. There was a paper from an Israeli group demonstrating that neural progenitors administered into the EAE model have a therapeutic effect that is mediated through immune modulation, however, relatively little work has been performed identifying the cell-to-cell interactions that are associated with such immune modulation.
Recently a paper by Knight et al. Cross-talk between CD4(+) T-cells and neural stem/progenitor cells. Knight et al. J Neurol Sci. 2011 Apr 12 attempted to investigate the interaction between immune cells and neural stem cells and vice versa. The investigators developed an in vitro system in which neural stem cells were incubated with CD 4 cells of the Th1 (stimulators of cell mediated immunity), Th2 (stimulators of antibody mediated immunity) and Th17 (stimulators of inflammatory responses) subsets. In order to elucidate the impact of the death receptor (Fas) and its ligand (FasL), the mouse strains lpr and gld, respectively, were used.
The investigators showed that Th1 type CD4 cells were capable of directly killing neural stem cells in vitro. Killing appeared to be independent of Fas activation on the stem cells since gld derived T cells or lpr derived neural stem cells still participated in killing. Interestingly, neural stem cells were capable of stimulating cell death in Th1 and Th17 cells but not in the Th2 cells. Killing was contact dependent and appeared to be mediated by FasL expressed on the neural stem cells. This is interesting because some other studies have demonstrated that FasL found on hematopoietic stem cells appears to kill activated T cells. In the context of hematopoietic stem cells this phenomena may be used to explain clinical findings that transplanting high numbers of CD34 cells results in a higher engraftment, mediated in part by killing of recipient origin T cells.
The finding that neural stem cells express FasL and selectively kill inflammatory cells (Th1 and Th17) while sparing anti-inflammatory cells (Th2) indicates that the stem cells themselves may be therapeutic by exerting an immune modulatory effect. One thing that the study did not do is to see if differentiated neural stem cells would mediate the same effect. In other words, it is essentially to know if the general state of cell immaturity is associated with inhibition of inflammatory responses, or whether this is an activity specific to neurons. As mentioned above, previous studies have demonstrated that mesenchymal stem cells (MSC) are capable of eliciting immune modulation through a similar means. Specifically, MSC have been demonstrated to stimulate selective generation of T regulatory cells. This cell type was not evaluated in the current study, however some activities of Th2 cells are shared with Treg cells in that both are capable of suppressing T cytotoxic cell activation. In the context of explaining biological activities of stem cell therapy studies such as this one stimulate the believe that stem cells do not necessarily mediate their effects by replacing damaged cells, but by acting on the immune system. Theoretically, one of the reasons why immature cells are immune modulatory in the anti-inflammatory sense may be because inflammation is associated with oxidative stress. Oxidative stress is associated with mutations. Conceptually, the body would want to preferentially protect the genome of immature cells given that the more immature the cells are, the more potential they have for stimulation of cancer. Mature cells have a limited self renewal ability, whereas immature cells, given they have a higher potential for replication are more likely to accumulate genomic damage and neoplastically transform.
AuxoCell Laboratories Licenses Umbilical Cord Tissue Stem Cell Service to PerkinElmer’s ViaCord
Viacord Press Release
Cord blood private banking involves storing your own cord blood mononuclear cells in case you need them later. Cord blood public banking involves banking the cells into a public pool so that if others need them, they have access to them. In some ways it seems like cord blood private banking is based more on hope than on reality. The majority of uses of cord blood are in leukemias. In patients with leukemia you need to use the cord blood of a related or unrelated donor, but rarely if ever do you want to use your own cord blood because it may have the leukemic mutations in it that caused the leukemia to appear in the first place. Therefore, the majority of cord blood banking is based on the belief that in the future the FDA will allow for procedures to take your banked cord blood, manipulate it to generate certain tissues in vitro and then reimplant those tissues back in you if you need them. There are of course exceptions to this. For example, there are clinical trials using your own cord blood for the treatment of cerebral palsy. Specifically, Georgia Health Sciences University is doing a 40 patient cord blood study in patients with cerebral palsy who have stored their own cord blood http://www.clinicaltrials.gov/ct2/show/NCT01072370. Additionally, Joanne Kurtzberg from Duke is performing an 120 patient study in children with cerebral palsy that have stored their own cord blood http://www.clinicaltrials.gov/ct2/show/NCT01147653. Other diseases are also being explored experimentally. Clinical trials are also being performed using patient’s own cord blood for type 1 diabetes. A group in Germany is doing a 10 patient trial http://www.clinicaltrials.gov/ct2/show/NCT00989547 and a group in Florida recently completed a 23 patient trial http://www.clinicaltrials.gov/ct2/show/NCT00305344.
Thus at present the field of private cord blood banking may have some very high future potential. Large companies are realizing this and accordingly are moving into this space. Perkin Elmers announced today that it has licensed technologies patented by AuxoCell Laboratories involving processing and storage of mesenchymal stem cells from the umbilical cord. As we discussed previously on the Cellmedicine website, the umbilical cord possesses mesenchymal stem cells that are in some ways more potent than bone marrow mesenchymal stem cells because they are more immature. The licensing of this technology will allow for Perkin Elmers to deliver to customers the ability to bank not only hematopoietic stem cells but also mesenchymal stem cells. There are many uses for mesenchymal stem cells. In fact numerous clinical trials have been performed using autologous mesenchymal stem cells for conditions ranging from heart failure, to graft versus host, to spinal cord injury.
“AuxoCell is pleased to partner with PerkinElmer’s ViaCord in offering umbilical cord tissue banking and expand our strategic partnerships to bring novel stem cell therapies from the bench to the bedside,” said Kyle Cetrulo, chief operating officer of AuxoCell Laboratories, Inc. “Partnering with ViaCord was an easy decision. They are the first family bank in the United States to freeze treatment-ready cord tissue stem cells upon arrival at the lab, which enables them to be ready for immediate use, if needed.”
“ViaCord is excited to offer another source of stem cells to our customers and believe we have found an excellent partner in AuxoCell. The agreement grants ViaCord’s customers exclusive access, in family banking, to expanding MSCs derived from cord tissue through AuxoCell’s elite patents,” said Morey Kraus, ViaCord’s chief scientific officer. “AuxoCell’s proprietary and validated manufacturing protocols will assist ViaCord in offering the very best in stem cell banking.”
Pluristem to develop stem cell therapy on its own: CEO
Anand Basu, Reuters
Pluristem is an Israeli company that is publicly traded on NASDAQ and has been working on a “universal donor” stem cell therapy that originates from cord blood mesenchymal stem cells. Key to Pluristem’s intellectual property are a series of patents on three dimensional bioreactors that allow for mass production of these cells. Interestingly, it is unclear to us who holds the intellectual property on the cells themselves. For example, Osiris holds the patents to many types of mesenchymal stem cells, ViaCell holds patents on some of the placental and cord blood mesenchymal cells, Celgene also holds patents on some of the cord blood and Wharton’s Jelly mesenchymal stem cells. Nevertheless, Pluristem has been pushing forward in development treatments, initially for post bone marrow transplant hematopoietic engraftment, and more recently for treatment of the terrible condition critical limb ischemia, which causes amputations in approximately 150,000 patients per year in the USA. Currently Pluristem planning to conduct its Phase II/III trials for critical limb ischemia in the second part of 2011. Given the success of the company in its clinical development programs, the CEO Zami Aberman recently announced that they will be working on their own towards commercialization. This is in contrast to other deals that we have seen in the recent past, such as the $1.7 billion deal between Pharma company Cephalon and the Australian stem cell company Mesoblast.
The ability to general large number of mesenchymal stem cells is a very important feature that gives the company a competitive edge over others in the space. Specifically, the use of bioreactor technologies allows for much higher production yields and a lower cost of production. Although the patent situation is somewhat uncertain for Pluristem, at the end of the day, numerous jurisdictions do not allow patenting of cells, so it may be feasible that the bioreactor patents that Pluristem has may be sufficient to protect the company as it is growing.
Mr. Aberman stated in a recent interview with Reuters “We do not need to raise money and we have sufficient capital to move the company to the end of Phase III studies,” Pluristem, which raised about $38 million in a public offering last month, plans to start a Phase II/III trial in both Europe and the United States to treat critical limb ischemia (CLI) in the second half of the year. He continued “We have been approached by a variety of pharmaceutical companies interested in cooperating not only on CLI but (also) for additional indications like inflammatory bowel disease, multiple sclerosis and orthopedic indication. However currently we are focusing on finding a marketing partner once our pivotal trials are underway. ”
In contrast to other companies that are working in this space and require processing of the patient’s own bone marrow as a source of stem cells, the Pluristem approach revolves around the concept of universal donor stem cells that are stockpiled and ready for use.
“The fact that we can do the treatment on demand because we have an off-the-shelf product is crucial, since CLI patients require immediate treatment,” Aberman said.
There have been previous studies performed in critical limb ischemia using mesenchymal stem cells. Mesenchymal stem cells can be used either autologous or allogeneically (meaning from another donor). Below we will list some of them.
For example, In 2010 Lasala et al reported combination cell therapy including EPCs and mesenchymal stem cells (a source of pericytes progenitors and angiogenic regulators) may represent a preferential stimuli for the development of blood vessels. In this phase I clinical trial, patients with LI were infused with a cell product consisting of autologous bone marrow-derived mononuclear and mesenchymal stem cells. After 10 2 months of follow-up, efficacy assessment demonstrated improvements in walking time, ankle brachial pressure, and quality of life. Concomitantly, angiographic and 99mTc-TF perfusion scintigraphy scores confirmed increased perfusion in the treated limbs. These results show that the use of a combination cell therapy appears to safe, and feasible in patients with CLI (Lasala, G.P., et al., Combination stem cell therapy for the treatment of severe limb ischemia: safety and efficacy analysis. Angiology, 2010. 61(6): p. 551-6.).
It was previously demonstrated in a rat model of critical limb ischemia that MSC are superior to bone marrow mononuclear cells in terms of angiogenic potency and limb preservation. This was suggested to be in part based on the ability of MSC to withstand the ischemic environment better than bone marrow mononuclear cells, as well as their ability to differentiate not only into endothelium but also smooth muscle (Iwase, T., et al., Comparison of angiogenic potency between mesenchymal stem cells and mononuclear cells in a rat model of hindlimb ischemia. Cardiovascular research, 2005. 66(3): p. 543-51). A comparison between bone marrow mononuclear cells and bone marrow MSC was made in 41 patients with CLI who had type II diabetes. The ulcer healing rate of the BMMSC group was significantly higher than that of BMMNCs at 6 weeks after injection (P=0.022), and reached 100% 4 weeks earlier than BMMNC group. After 24 weeks of follow-up, the improvements in limb perfusion induced by the BMMSCs transplantation were more significant than those by BMMNCs in terms of painless walking time (P=0.040), ankle-brachial index (ABI) (P=0.017), transcutaneous oxygen pressure (TcO(2)) (P=0.001), and magnetic resonance angiography (MRA) analysis (P=0.018). There was no significant difference between the groups in terms of pain relief and amputation and there was no serious adverse events related to both cell injections. The authors concluded that BMMSCs therapy may be better tolerated and more effective than BMMNCs for increasing lower limb perfusion and promoting foot ulcer healing in diabetic patients with CLI (Lu, D., et al., Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: A double-blind, randomized, controlled trial. Diabetes research and clinical practice, 2011).
The ability to use universal donor cells in the context of critical limb ischemia is advantageous in that the bone marrow of patients does not need to be punctured. Usually patients with critical limb ischemia have numerous co-morbidities that makes bone marrow aspiration extremely difficult. Additionally, it is almost impossible to performed secondary transplants. In the area of critical limb ischemia, it may be important to perform multiple injections for additional therapeutic effects. Another advantage of universal donor cells is that many times the bone marrow of patients with critical limb ischemia are insufficient in ability to produce cytokines or stimulate angiogenesis in vitro or in vivo. The administration of selected cells that are purified for maximal potency possesses a therapeutic advantage. Disadvantages of the Pluristem approach include the possibility of knock-off technologies due to the lack of a patent on composition of matter on the cells. Worse yet, companies such as Celgene and now PerkinElmers possess intellectual property on cells derived from the placental matrix. It will be interesting to see how these patents play out in terms of enforceability.
StemCells, Inc. Initiates World’s First Neural Stem Cell Trial In Spinal Cord Injury
StemCells Inc Press Release
StemCells Inc announced today they are initiating a clinical trial using their fetal derived neural progenitor cells for the treatment of spinal cord injuries. Previously the company had reported that their stem cells, called HuCNS-SC, are capable of differentiating into various neural lineage cells including neurons, oligodendrocytes, and astrocytes. The fact that HuCNS-SC are derived from fetal sources allows them to possess a lower ability to stimulate immune responses, therefore, the cells can be used as an “off the shelf” product.
According to the company “The Company’s preclinical research has shown that HuCNS-SC cells can be directly transplanted in the central nervous system (CNS) with no sign of tumor formation or adverse effects. Because the transplanted HuCNS-SC cells have been shown to engraft and survive long-term, this suggests the possibility of a durable clinical effect following a single transplantation. StemCells believes that HuCNS-SC cells may have broad therapeutic application for many diseases and disorders of the CNS, and to date has demonstrated human safety data from completed and ongoing studies of these cells in two fatal brain disorders in children.”
The proposed study will be conducted at the Balgrist University Hospital, in Zurich, which is a private, non-profit institution managed in accordance with economic principles. The clinic has three key areas of expertise: it is a highly specialised centre providing examination, treatment and rehabilitation opportunities to patients with serious musculoskeletal conditions; it is responsible for training future doctors studying at the University of Zurich in orthopaedics and paraplegiology and providing professional training for doctors and medical staff in the domains of orthopaedics, paraplegiology, rheumatology, anaesthesiology and radiology; it is a research centre dedicated to improving quality for healthcare in the future. The number of patients or inclusion/exclusion criteria for the trial was not mentioned in the press release. However a look at clinicaltrials.gov reveals the following:
The study is a 12 patient Phase I/II trial in which treated patients will also receive immune suppression so that the transplanted cells will not be rejected. The trial has the following inclusion/exclusion criteria:
Inclusion Criteria:
• T2-T11 thoracic spinal cord injury based on American Spinal Injury Association (ASIA) level determination by the principal investigator (PI)
• T2-T11 thoracic spinal cord injury as assessed by magnetic resonance imaging (MRI) and/or computerized tomography (CT)
• ASIA Impairment Scale (AIS) Grade A, B, or C
• Minimum of six weeks post injury for the initiation of screening
• Must have evidence of preserved conus function
• Must be at stable stage of medical recovery after injury
Exclusion Criteria:
• History of traumatic brain injury without recovery
• Penetrating spinal cord injury
• Evidence of spinal instability or persistent spinal stenosis and/or compression related to initial trauma
• Previous organ, tissue or bone marrow transplantation
• Previous participation in any gene transfer or cell transplant trial
• Current or prior malignancy
Success in treatment of spinal cord injury has been reported in the peer reviewed literature by Cellmedicine in which a patient was treated with a combination of cord blood hematopoietic and placental matrix mesenchymal stem cells http://www.intarchmed.com/content/pdf/1755-7682-3-30.pdf.
The advantage of the approach proposed by StemCells Inc is that only one injection of stem cells may be necessary . The disadvantage is that while the stem cells may generate neurons, it is difficult to imagine how one source of stem cells alone can recapitulate and accelerate the multicellular process involved in healing of the spinal cord.
Treatment of spinal cord injuries using stem cells is also underway by the company Geron who uses embryonic stem cell derived oligodendrocytes in patients with spinal cord injury.
Two previous trials have been reported in the area of spinal cord injury that used mesenchymal stem cells exclusively. In 2006 the group of Movilgia et al from Argentina treated two patients with spinal cord injury using an interesting protocol of T cell plus MSC. Forty-eight hours prior to NSC implant, patients received an i.v. infusion of 5 x 10(8) to 1 x 10(9) AT cells. NSC were infused via a feeding artery of the lesion site. Safety evaluations were performed everyday, from the day of the first infusion until 96 h after the second infusion. Patient 1 was a 19-year-old man who presented paraplegia at the eight thoracic vertebra (T8) with his sensitive level corresponding to his sixth thoracic metamere (T6). He received two AT-NSC treatments and neurorehabilitation for 6 months. At present his motor level corresponds to his first sacral metamere (S1) and his sensitive level to the fourth sacral metamere (S4). Patient 2 was a 21-year-old woman who had a lesion that extended from her third to her fifth cervical vertebrae (C3-C5). Prior to her first therapeutic cycle she had severe quadriplegia and her sensitive level corresponded to her second cervical metamere (C2). After 3 months of treatment her motor and sensitive levels reached her first and second thoracic metameres (T1-T2). No adverse events were detected in either patient (Moviglia, G.A., et al., Combined protocol of cell therapy for chronic spinal cord injury. Report on the electrical and functional recovery of two patients. Cytotherapy, 2006. 8(3): p. 202-9).
Pal et al from Stemeutics in India reported 30 patients with clinically complete SCI at cervical or thoracic levels were recruited and divided into two groups based on the duration of injury. Patients with <6 months of post-SCI were recruited into group 1 and patients with >6 months of post-SCI were included into group 2. Autologous BM was harvested from the iliac crest of SCI patients under local anesthesia and BM MSC were isolated and expanded ex vivo. BM MSC were tested for quality control, characterized for cell surface markers and transplanted back to the patient via lumbar puncture at a dose of 1 x 10(6) cells/kg body weight. Three patients had completed 3 years of follow-up post-BM MSC administration, 10 patients 2 years follow-up and 10 patients 1 year follow-up. Five patients have been lost to follow-up. None of the patients have reported any adverse events associated with BM MSC transplantation (Pal, R., et al., Ex vivo-expanded autologous bone marrow-derived mesenchymal stromal cells in human spinal cord injury/paraplegia: a pilot clinical study. Cytotherapy, 2009. 11(7): p. 897-911)
A search of clinicaltrials.gov for ongoing trials using stem cells in patients with spinal cord injury reveals the following:
1. Cairo University is performing a Phase I/II trial in 80 patients with spinal cord injury who are receiving autologous bone marrow derived stem cells. The trial includes patients that are treated with stem cells and receive physical therapy versus patients receiving physical therapy alone. The trial has completed enrollment and recruited patients who had injury 8 months to 3 years before entering the trial.
2. RNL Bio from Korea is performing a Phase I study on 8 spinal cord injury patients who had their injuries more than two months before entering the study. The cells administered are 40 million autologous adipose derived cells, given intravenously. The trial enrollment is completed and the Principle Investigator is Dr. SangHan Kim, MD from the Anyang Sam Hospital.
3. International Stemcell Services Limited from India is doing a 12 patient Phase I/II trial administering autologous bone marrow into patients after spinal cord injury. The trial enrollment is completed and the Principle Investigator is Dr.Arvind Bhateja, from the Sita Bhateja Speciality Hospital.
4. TCA Biosciences from Louisiana is performing a 10 patient Phase I trial using autologous bone marrow mesenchymal stem cells. The trial enrollment is completed.
5. The Memorial Hermann Healthcare System is doing a study using autologous bone marrow cells in children aged 1-15 using autologous bone marrow cells. The study plans to enroll 10 patients.
6. The Hospital Sao Rafael from Brazil is doing a 10 patient study using autologous bone marrow in spinal cord injury patients.
This exploration of clinicaltrials.gov tells us that relatively little is being performed in terms of stem cell therapy for spinal cord injury. Given the success of Cellmedicine at treating this condition, it will be interesting to see the outcomes of the other ongoing trials.
Stem Cell Technique Could Help Those With Fast-aging Disease
February 23, 2011
Hutchinson-Gilfod progeria syndrome is a fast-aging disease that is rare, has no cure, and is fatal. Children with this disease undergo rapid aging and generally do not live to their teens. It is caused by a single mutation of the LMNA gene, which results in a defect in the production of lamin A, a protein which is required to build the membranous shell around genetic material. The majority of children with Hutchinson-Gilford progeria die from complications pertaining to hardening of their blood vessels. Fortunately, this disease is very rare, as only 64 children in the world are known to have it, however due to the small number of patients suffering from this disease, there are very few opportunities to study it and thus form any type of treatment.
New technology has introduced a new possibility in the treatment of this progeria. In the past five years, scientists have begun using targeted retroviruses that selectively alter DNA in order to cause a regression of cells from the muscle or skin into their stem cell form, pluripotent stem cells. Pluripotent stem cells have the potential to form various different types of cells in the body, depending on where they are transplanted to.
The cells that were taken from the patients were regressed back to their pluripotent stem cell stage by a research team led by Juan Carlos Izpisua Belmonte and Guanghui Liu at the Salk Institute in La Jolla, California. The researchers found that after this regression, the cells from the patients no longer contained the information that corresponded to diseased cells. However, despite the absence of the mutation in the stem cell state, these cells would not necessarily be rid of the defect which sets the fate for the disease. The resetting of the cells does allow for the scientists to study the progression of the disease its beginning.
Liu’s lab is working on a technique that will fix the genetic mutation responsible for the progeria in hopes of developing a treatment or even a cure for the disease. “Hopefully our efforts will be useful to generate … [non-symptomatic] progeria cells and help those progeria patients in the near future,” he said.
PRECISE: Adipose-derived stem cells show utility as therapy
Cardiology Today
PRECISE is The Randomized Clinical Trial of Adipose-Derived Stem Cells in Treatment of Non Revascularizable Ischemic Myocardium, a double blind, placebo-controlled trial involving 27 patients with chronic ischemic heart disease with HF, angina or both, who were not eligible for percutaneous or surgical revascularization. The patients in the study underwent a liposuction to remove adipose tissue from their abdomen, the stem cells were separated and then reinjected directly into the heart. Placebo patients received the same treatment however were injected with placebo in place of stem cells. “These patients were not even able to be transplanted. So these were very high-risk, no-option patients,” said Francisco Fernández-Avilés, MD, with the department of cardiology, Hospital General Universitario Gregorio Marañón, Madrid, and PRECISE investigator.
The patients who were treated with stem cells had improved infarct size at 6 months and peak oxygen consumption compared to the placebo patients. “In my opinion, the results of the PRECISE trial are good enough to reconsider the possibility to start a larger scale randomized trial comparing cells to placebo in terms of left ventricular function, mainly clinical outcomes [like] mortality, HF and ischemia,” Fernández-Avilés said. For the years ahead, Fernández-Avilés said in patients with chronic HF and viability, the answer for stem cell therapy is adipose tissue, “and for patients with no viability, in my opinion, we need more basic investigation to find more effective cells.”
Stem Cells Help Women Regrow Breasts After A Mastectomy
By Lucy Johnston
Scientists in the UK and Australia have been implementing a new technique to benefit women who have had a mastectomy to remove cancerous cells. The technique involves placing a special plastic mould under the skin and then injecting the area with the patient’s own stem cells. The cells are cultured from adipose tissue that is removed from the patient by liposuction. The stem cells are removed from the fat tissue and grown to a larger number, then recombined with the fat and injected back into the body. Results generally take from six months to a year, over which the fat and stem cells grow slowly until new breast tissue is formed. Since the tissue is grown by the patients’ own body, the breasts look and feel natural and are much more comfortable than silicone implants.
The treatment was discovered by observing the way the body reacts to wounds. “Nature doesn’t like a vacuum,” said Professor Wayne Morrison of Melbourne University, who has performed the procedure himself, “so the chamber itself, because it is empty, tends to be filled in by the fat. We observed this and decided it could be used to help treat women who’d lost their breasts to cancer. Fat cells can grow to fill a void in the same way that the body repairs tissue damage. Our research shows fat continued to grow until it had filled the area where there had once been a natural breast. We attach the area to a blood supply from the chest or under the arm which helps the fat grow. The mould used by surgeons helps create a breast shape in which the fat forms.”
The current treatment for mastectomy patients involves taking tissue from the buttock to form a new breast. The results of this treatment are variable, however, and the implementation of the use of stem cells will hopefully improve the outlooks for women. The treatment could also have potential for cosmetic surgeries as well, possibly replacing saline or silicone implants, which have been associated with various side effects.
Professor Morrison said: “We hope the technology will have a significant impact around the world. There are a lot of women who don’t have reconstructive surgery for whatever reason or have silicone breast implants but this will give them their own tissue back.”
The patients that have been treated so far have had very impressive results, according to Professor Kefah Mokbel, consultant breast surgeon at St. George’s Hospital, London. The plastic scaffolding used as a mould must be removed surgically, however the procedure is minimally invasive. Researchers hope to develop a biodegradable scaffold which will dissolve once the implant has grown. The treatment is also not used on women who have been cancer free for less than a year, in order to prevent the stem cells from causing further tumor growth.
