Peng et al. Hepatology.
The liver is the most regenerative solid organ in the body. One can resect 2/3 of the liver and it will still regenerate back to normal size. There have been several experimental studies in animals where induction of liver injury is treated by administration of bone marrow stem cells. A video describing this may be seen at this link http://www.youtube.com/watch?v=XGdehdRApb0. Previous use of bone marrow cells in patients with liver failure has been described in a Japanese publication that is presented in this video http://www.youtube.com/watch?v=DdH6Mm4w98I.
A recent study Peng et al. Autologous bone mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B: Short-term and long-term outcomes. Hepatology. 2011 May 23 from the 3rd Affiliated Hospital of Sun Yat-sen University, in GuangZhou, China reported outcomes of 53 patients with hepatitis B induced liver failure treated with 120 ml of their own bone marrow stem cells infused via the hepatic artery. These patients were compared to 105 control patients that were matched for age, gender, and liver enzymes. Additionally, the functional index of liver failure, the Model for End-Stage Liver Disease (MELD) score, was matched between the treated and control groups.
Bone marrow stem cells were isolated without complications. The cells were administered as a slow infusion into the hepatic artery. Given that hepatitis is associated with an increase in hepatic cancer, one of the concerns of bone marrow stem cell administration into this patient population is the theoretical possibility of accelerating tumor formation. This appeared not to be the case. Specificallyt, follow-up at 192 weeks post treatment revealed no differences in incidence of hepatocellular carcinoma (HCC) or mortality between the two groups. Additionally, there were no significant differences in the incidence of HCC or mortality between patients with and without cirrhosis in the transplantation group. In terms of efficacy, it appeared that 2 to 3 weeks after administration of bone marrow stem cells, the levels of ALB, TBIL, PT and the MELD score of patients who received stem cells were significantly improved as compared to control patients. Improvements where maintained in the majority of patients.
These data support the possibility of using autologous stem cells in the treatment of liver failure. One possible new and less invasive method would be to mobilize the existing stem cells of the patient by administering drugs such as G-CSF (Neupogen) that trigger entry of bone marrow stem cells into circulation. The therapeutic activity of stem cell mobilization was demonstrated by 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 who demonstrated that 5 day administration of G-CSF had therapeutic effects in the d-galactosamine-stimulated liver failure model.
Bone Marrow Stem Cells Successful For Liver Failure Caused by Hepatitis B
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.”
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 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.
Increasing Efficacy of Stem Cell Therapy for Spinal Cord Injury
Jin et al. Spine (Phila Pa 1976).
Clinical trials of stem cells for treatment of spinal cord injury are currently being conducted in the United States and abroad. For example, the Covington Louisiana company TCA Cellular Therapy LLC is recruiting 10 patients with spinal cord injury to receive intrathecal infusion (lumbar puncture) of autologous, ex vivo expanded bone marrow-derived mesenchymal stem cells. Completed clinical trials have demonstrated some rationale that stem cells may be useful. For example, Kumar et al. (Autologous bone marrow derived mononuclear cell therapy for spinal cord injury: A phase I/II clinical safety and primary efficacy data. Exp Clin Transplant. 2009 Dec;7(4):241-8) reported on 297 spinal cord injury patients that were treated with their own bone marrow cells injected intrathecal. 33% of the patients reported an objective improvement.
As with other clinical trials of stem cell therapy, it appears that in the area of spinal cord injury there still remains room for improvement. We at Cellmedicine have reported a stunning improvement in a spinal cord injury patient by using a combination of CD34 and mesenchymal stem cells, which was recently published http://www.intarchmed.com/content/pdf/1755-7682-3-30.pdf. Unfortunately this was only one patient and more studies are required.
In an attempt to improve efficacy of stem cell therapy for spinal cord injury, a group from the Department of Neurosurgery, Spine and Spinal Cord Institute, at the Yonsei University College of Medicine, Seoul, Republic of Korea, has created an artificial method of increasing growth factor production from stem cells of the nervous system called neural progenitor cells. Previous studies have shown that neural progenitor cells are capable of treating several models of spinal cord injury, however their effects appear to be transient. Vascular endothelial growth factor (VEGF) is a protein that increases blood vessel production in tissues and has been previously demonstrated to stimulate integration of nervous system cells after spinal cord injury. Since increasing VEGF production could hypothetically increase efficacy of neural stem cells, a series of experiments were performed in order to generate modified neural stem cells which have enhanced VEGF production.
It is known that insertion of a gene into a cell can cause the cell to produce the protein made by the gene. So theoretically all the researchers had to do is to transfect (insert) the VEGF gene into the neural stem cells and the neural stem cells would be more effective. The problem with this is that too much VEGF can have negative effects. A more attractive approach would be to program the progenitor cells in such a manner so that they produce VEGF only when it is necessary. During spinal cord injury, the area of damage is associated with reduced oxygen, a condition called hypoxia. Ideally one would want to engineer the stem cells in a manner so that they produce VEGF only during times of hypoxia. One way of doing this is to control the expression the gene by using an inducible promoter.
Promoters are pieces of DNA that control expression of genes that are in front of them. Some promoters always turn on gene expression (these are called constitutive promoters), others turn on expression only under specific conditions (these are called inducible promoters. The promoter that turns on erythropoietin is an inducible promoter. Erythropoietin is made by the kidney and stimulates production of red blood cells. Its expression is turned on under conditions of lack of oxygen. This is why people who live in high altitudes have higher expression of erythropoietin. The scientists in the current publication developed a genetically engineered neural stem cell that contains the VEGF gene under control of the erythropoietin promoter. What this means is that the cells will be producing VEGF only under conditions of hypoxia. In order to selectively detect the areas of hypoxia, the scientists also developed stem cells that have the luciferase gene in front of the erythropoietin promoter. Luciferase is a protein that generates light and allows for easy detection in vitro and in vivo of the hypoxic cells.
The scientists found that the stem cells administered during hypoxia generated significantly higher concentrations of VEGF, which was associated with the promoter being turned on, as assessed by luciferase expression. Furthermore, rats receiving the VEGF expressing stem cells possessed a significantly lower amount of nerve damage and higher ability to recuperate after spinal cord injury.
These data suggest that it is feasible to combine inducible promoters with stem cells in order to augment various activities of the stem cells. This concept could be applied to numerous settings. For example, mesenchymal stem cells are known to selectively migrate to areas of inflammation. In the setting of cancer, mesenchymal stem cells could be transfected with genes that are encoding toxic substances. This way chemotherapy could be targeted only to cancer cells and therefore have a better safety profile.
Gene therapy has failed to a large extent because of lack of ability to control where the genes are administered. It may be possible that advancements in stem cell technologies will allow for a rebirth of gene therapy in that the stem cells may be used to deliver genes only to the tissues where they are needed.
Stem cell therapy shows early promise: Celgene
Crohn’s disease is a favorite amongst mesenchymal stem cell
development companies. This may be because on the one hand, this type of stem
cell possesses anti-inflammatory properties, and on the other hand it has the
potential to regenerate injured tissue. Additionally since the quality of life
of patients with advanced Crohn’s Disease is so poor, and current treatments are
generally ineffective at addressing the root cause, that new treatments usually
receive much support from regulatory agencies. Crohn’s disease is characterized
as a chronic inflammatory condition of the gastrointestinal tract. It is
believed to affects almost one million people in the United States.
Today Celgene announced Phase I safety data on its
placental mesenchymal stem cell product PDA-001 in a trial of 12 patients. The
patients suffered from active moderate-to-severe Crohn’s and were unresponsive
to at least one prior conventional therapy. The treatment with stem cells
comprised two infusions of PDA-001 one week apart. The patients were divided
into 2 groups with 6 patients being administered a lower number of cells and six
a higher number.
According to Celgene, "The study met its primary safety
goal and demonstrated encouraging signs of clinical benefit, including clinical
remission among four patients in the low dose group". Interestingly the company
declined to speculate on why the lower number of cells elicited superior
benefit. As an interesting aside, the company Osiris Therapeutic conducted a
similar clinical trial in Crohn’s Disease using stem cells derived not from
placenta but from bone marrow sources.
The CEO of Celgene’s Cellular Therapeutics unit, Dr. Robert
Hariri stated "We are encouraged that in these patients with Crohn’s disease our
unique, placenta-derived therapies show signs of clinical benefit," he continued
"We will continue to aggressively pursue the clinical development of this and
other cellular therapies derived from what we see as one of the richest sources
of uniquely functional and versatile cells."
The company anticipates moving into Phase II clinical
trials not only in the area of Crohn’s but also in other degenerative
indications.
It is an interesting point that the cells were administered
intravenously. There are some groups that believe stem cells only work if
administered locally. This study suggests that the need for local injection may
not be as important as some others believe. Additionally, since companies like
Cellmedicine use various mesenchymal stem cell sources, the current results
provide US-based scientific evidence supporting at least the rationale for this
approach.
Stem Cells Might Reverse Heart Damage From Chemo
One of the great findings of regenerative medicine was that organs previously believed to be incapable of healing themselves actually contain stem cells that in response to injury cause some degree of healing. The problem being that these "endogenous healing mechanisms" are usually too small to mediate effects that are visible at the clinical level. For example, the brain was considered to have very limited ability to heal itself after damage. Recent studies that have allowed for observation of brain cells after experimental strokes have led to the discovery of brain stem cells in the dendate gyrus and subventricular zones of the brain, stem cells that start to multiple after a stroke. Interestingly, various hormones such as human chonrionic gonadotropin, are capable of stimulating brain stem cell multiplication. This is currently being used in clinical trials for stroke by the company Stem Cell Therapeutics.
In the area of heart failure, it was also believed that once cardiac tissue is damaged, the only repair process that the body performs is production of scar tissue, which is pathological to the patient. While this scar tissue is found in the majority of the injured area, molecular studies have revealed the existence of cardiac specific stem cells, which start to multiply after injury and serve to repair, albeit in small amounts, the infarct area.
One way to augment endogenous repair processes is to administer stem cells from the bone marrow, which are known to produce various growth factors that assist the tissue-specific stem cell in mediating its activity. Another way is to physically extract the tissue specific stem cells, expand them outside of the body and reimplant them into the damaged area.
In a recent publication in the journal Circulation, Piero Anversa, M.D., director, Center for Regenerative Medicine, Departments of Anesthesia and Medicine and Cardiovascular Division, Brigham and Women’s Hospital, Boston and Roberto Bolli, M.D., chief, cardiology, and director, Institute of Molecular Cardiology, University of Louisville, Kentucky, describe the use of cardiac specific stem cells in treatment of animals whose hearts of been damaged by the chemotherapeutic drug doxorubicin.
Doxorubicin is a chemotherapeutic drug that is mainly used in the treatment of breast, ovarian, lung, and thyroid cancers, as well as for neuroblastoma, lymphoma and leukemia. One of the main limiting factors to increasing the dose of doxorubicin to levels that can lead to tumor eradication is that it causes damage to the heart muscle, the myocardium.
In the published study, the investigators expanded the cardiac specific stem cells from rats, gave the rats high doses of doxorubicin and in some rats injected back cardiac specific stem cells, whereas other rats received control cells. The rats that received the cardiac specific stem cells had both preservation of cardiac function, and also regeneration of the damaged heart tissue. This is an important finding since the type of damage that doxorubicin does to the heart is different from other types of heart damage that have been studies, such as the damage that occurs after a heart attack. These data seem to suggest that stem cell therapy may be useful in a variety of injury situations.
"Theoretically, patients could be rescued using their own stem cells," said study author Dr. Piero Anversa, director of the Center for Regenerative Medicine at Brigham and Women’s Hospital in Boston. Dr. Aversa is one of the original discoverers of the cardiac specific stem cell when he published experiments in dogs demonstrating multiplication of cells in the myocardium that seem to have ability to generate new tissue after damage (Linke et al. Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc Natl Acad Sci U S A. 2005 Jun 21;102(25):8966-71).
"A Phase 1 clinical trial using a similar procedure in people is already under way", said Dr. Roberto Bolli, chief of cardiology and director of the Institute of Molecular Cardiology at the University of Louisville in Kentucky, who is heading the trial. The FDA has approved a Phase I clinical trial using cardiac specific stem cells in 30 patients who have congestive heart failure due to disseminated atherosclerosis. "In the trial, participants’ cardiac tissue will be harvested, the stem cells isolated and then expanded in vitro from about 500 cells to 1 million cells over several weeks", Bolli explained. "Several months after the patient has undergone bypass surgery, the stem cells will be re-injected." A similar clinical trial is being performed at Cedars Sinai in Los Angeles.
While the problems of tissue extraction (which is performed by an invasive procedure requiring biopsy of heart tissue) and cost of expansion are still formidable hurdles to widespread implementation, it is believed that the clinical evidence of a therapeutic response will open the door to other avenues of expanding tissue specific stem cells, such as administration of growth factors that can accomplish this without need for cell extraction outside of the body.
Stem Cell as Anti-Aging “Medicine”
Medistem Inc issued a press release describing a collaborative publication between the University of California San Diego, Indiana University, University of Utah, the Dove Clinic for Integrative Medicine, Biotheryx, NovoMedix, The Bio-Communications Research Institute, The Center for Improvement of Human Functioning International and Aidan Products, discussing the contribution of circulating endothelial cells to prevention of aging. The publication also provided data showing that healthy volunteers who have been administered the food supplement Stem-Kine had a doubling of circulating endothelial progenitor cells.
The paper "Circulating endothelial progenitor cells: a new approach to anti-aging medicine?" is freely accessible. "Numerous experiments and clinical trials have been published describing the importance of these repair cells that the body possesses to heal internal organs," stated Dr. Doru Alexandrescu from Georgetown Dermatology, a co-author of the publication. "However, to our knowledge, this is the first comprehensive blueprint in the peer-reviewed literature of how this knowledge may be applied to the question of aging."
The paper summarizes publications describing correlations between decline of circulating endothelial cells and aging/deterioration of several organ systems. The main hypothesis of the publication is that the bone marrow generates a basal number of circulating endothelial cells that serve to continually regenerate the cells that line the blood vessels. Many diseases that are prevalent in aging such as Alzheimer’s are associated with dysfunction of the blood vessel’s ability to respond to various stimuli. This dysfunction is believed to be caused by diminished numbers of circulating endothelial progenitor cells.
Other conditions such as peripheral artery disease are also associated with reduction in this stem cell population, however, when agents are given that increase the numbers of these cells, the degree of atherosclerosis-mediated pathology is decreased. This was demonstrated in a study that administered the drug GM-CSF, which causes an increase in circulating endothelial progenitor cells in a manner similar to Stem-Kine. Unfortunately, drugs currently on the market that have this ability are very expensive and possess the possibility of numerous side effects. The Stem-Kine food supplement is sold as a neutraceutical and is made of natural ingredients that have already been in the food supply.
Another interesting point made by the paper was that the body modulates the number of circulating endothelial progenitor cells based on need. In stroke, the number of circulating endothelial progenitor cells markedly increases in response to the brain damage. Patients in which a higher increase is observed are noted to have a higher chance of recovery. Therapeutic interventions that contain endothelial progenitor cells such as administration of bone marrow cells after a heart attack, are believed to work, at least in part, through providing a cellular basis for creation of new blood vessels, a process called angiogenesis.
Patients with inflammatory conditions ranging from chronic heart failure, to type 2 diabetes, to Crohn’s disease are noted to have a reduction in these cells. The reduction seems to be mediated by the inflammatory signal TNF-alpha. Studies reviewed in the paper describe how administration of antibodies to TNF-alpha in patients with inflammatory conditions results in a restoration of circulating endothelial progenitor cells.
In addition to the possible use of Stem-Kine for restoration/maintenance of circulating endothelial progenitor cells, the publication discusses the possibility of using such cells from sources outside of the body, for example cord blood. Although it was previously thought that cord blood can be used only after strict HLA matching, recent work supports the idea that for regenerative medicine uses, in which prior destruction of the recipient immune system is not required, cord blood may be used without immune suppression or strict tissue matching. This is discussed in the following paper: Cord blood in regenerative medicine: do we need immune
suppression?.
Adenosine inhibits chemotaxis and induces hepatocyte-specific genes in bone marrow mesenchymal stem cells
Bone marrow cells contain several populations that are useful for regenerating injured/aged tissue. These cells include hematopoietic stem cells, mesenchymal stem cells, endothelial progenitor cells, and some argue, progenitor cells left over from embryonic periods that are still capable of differentiating into numerous injured tissue. It has been known for some time that bone marrow cells are capable of treating liver failure both in vitro and in early clinical trials, as can be seen on this video: Stem Cell Therapy for Liver Failure. Other types of stem cells useful for treatment of liver failure, such as cord blood stem cells, may be seen on this video: Cord Blood and Bone Marrow Stem Cells for Liver Failure.
One of the major questions with adult stem cell therapy is how do the stem cells go to where they are needed? Some people have made the argument that stem cells administered intravenously do not cause systemic effect because the majority get stuck in the lung and liver. Although cell sequestration is an issue, numerous studies have demonstrated therapeutic effects after intravenous administration of stem cells. Perhaps the most well-known stem cell homing molecule is stromal derived factor (SDF-1), which is made by injured and/or hypoxic tissue and causes stem cell mobilization and migration through activation of the CXCR4 receptor. The SDF-1/CXCR4 axis has been found in numerous conditions of tissue injury such as: stroke, heart attack, acoustic injured ear, liver failure, and post-transplant reconstitution of bone marrow. To understand how this “chemokine” works, the following video will describe it as relevant to stem cell repopulation post-irradiation: Homing of Stem Cells to Target Tissue
In a study published today scientists examined another signal made by injured tissue in order to assess whether it may act like SDF-1 and “call in” stem cells. The signal chosen was the amino acid adenosine, which is released from injured/necrotic cells. They found that adenosine did not by itself induce chemotaxis of mesenchymal stem cells (MSC) but dramatically inhibited MSC chemotaxis in response to the chemoattractant hepatocyte growth factor (HGF). Inhibition of HGF-induced chemotaxis by adenosine requires the A2a receptor and is mediated via up-regulation of the cyclic adenosine monophosphate (AMP)/protein kinase A pathway. Additionally, the investigators found that adenosine induces the expression of some key endodermal and hepatocyte-specific genes in mouse and human MSCs in vitro.
The ability of adenosine to modulate migration/differentiation processes implies that numerous paracrine/autocrine interactions are occurring during tissue injury. It will be critical to identify how to manipulate such factors to obtain maximal therapeutic responses.
