Stem cells that make blood are heavily concentrated in the bone marrow. These cells are called "hematopoietic stem cells". When patients with leukemia are given a bone marrow transplant, they first receive high doses of radiation and chemotherapy in order to kill both the leukemic cells, as well as the healthy blood cells in the bone marrow. Subsequently the patients are given healthy bone marrow from a patient that has been matched immunologically. The new bone marrow contains high numbers of stem cells that take over the task of making new blood cells for the body. In some situations the leukemia comes back, however a bigger cause of mortality is when the blood cells made by the new bone marrow start attacking the recipient. This is a condition called graft versus host.

One of the advancements in bone marrow transplantation was the use of stem cells collected from the blood instead of the bone marrow. While under normal circumstances there are very little hematopoietic stem cells circulating in the blood, it was observed many years ago that after administration of certain compounds, the number of stem cells in the blood increases. This led scientists to try to find agents that can be used in patients that make stem cells leave bone marrow and enter circulation. There are three reasons why this would be important. Firstly, the process of extracting bone marrow from donors is very difficult. It involves sometimes more than 30 punctures into the hip bone. Secondly, there is some evidence that when the stem cells are collected from the blood, they have less potential to stimulate graft versus host disease. Thirdly, outside of the context of transplantation, it is known that bone marrow stem cells have ability to accelerate healing of tissues. Thus if there was a drug that could induce stem cells to leave the bone marrow and enter circulation, this drug would have many benefits.

The first stem cell mobilizer to be approved was granulocyte colony stimulating factor (G-CSF). This is a protein that is made by many cells in the body, especially by cells of the immune system. G-CSF specifically tells the bone marrow cell to make more granulocytes, these are cells that fight infections. In the process of infection, cells of the immune system called macrophages, start to produce G-CSF in response to bacteria and cause production of granulocytes which can then go and fight the bacteria. Interestingly, it was found that G-CSF also would instruct the bone marrow stem cells to exit the bone marrow and enter circulation.

This led to a variety of studies demonstrating that G-CSF "mobilized" stem cells can be collected from the blood of donors and used as an alternative to harvesting of donor bone marrow. In the majority of hospitals that perform transplants, donor collection is now performed by mobilization of stem cells.

Studies have reported that stem cells mobilized by G-CSF appear to have some beneficial effects in patients who have had heart attacks. Other studies have shown that stem cells mobilized by G-CSF may help patients with heart failure due to poor blood supply to the heart. For example, Maier et al. published a paper (Myocardial salvage through coronary collateral growth by granulocyte colony-stimulating factor in chronic coronary artery disease: a controlled randomized trial. Circulation. 2009 Oct 6;120(14):1355-63) in which 52 patients suffering from coronary artery disease were given either placebo or G-CSF for 2 weeks. Increases in the blood supply to the heart, and heart function were observed in the treated patients.

Currently G-CSF sells more than a billion dollars a year for use in a variety of diseases. Since the original patents on G-CSF have expired, there has been a great interest in the development of other stem cell mobilizers. However, to develop newer drugs that cause mobilization, it may be worthwhile to discuss the mechanisms by which G-CSF induces this process. It is known that in transplantation of stem cells, that the recipient can receive stem cells intravenously, but somehow they home to the bone marrow. This homing mechanism is mediated by the protein stromal derived factor (SDF)-1, which is made at a stable rate by the other cells in the bone marrow that are not stem cells. The hematopoietic stem cells recognize concentrations of SDF-1 based on receptors called CXCR-4. When G-CSF is administered, numerous biochemical pathways are activated that seem to converge, at least in part, to disrupting the interaction between the SDF-1 made by the bone marrow and the CXCR-4 that is on the stem cells.

The company Anormed recognized the importance of this interaction and started making chemical drugs that would block it. As we stated, G-CSF causes a variety of biological effects, however, by selectively targeting the essential interaction, the ability to increase mobilization should theoretically be more potent. Indeed, Anormed developed the drug Mozobil, which appears to be 10-100 times more potent than G-CSF at mobilizing stem cells, and was sold to Genzyme in a deal worth half a billion dollars. Mozobil received FDA approval and is currently used alone or sometimes in combination with G-CSF.
Recognition of the importance of the SDF-1-CXCR4 interaction led the company NOXXON to develop drugs to target this. However, unlike Anormed, which used conventional small molecules, NOXXON used a new technology called Aptamers, which are nucleic acids that can be engineered to specifically block interactions between proteins. The process of generating aptamers to target proteins involves selection in vitro, which can be accomplished at a more rapid rate as compared to what can be done for small molecules.

Today NOXXON announced that is has successfully administered its NOX-A12 aptamer-based mobilizer to healthy volunteers as part of a Phase I clinical trial. Usually the purpose of a Phase I trial is to determine the distribution of a drug in the human body, and to test for possible adverse effects. The dose chosen from a Phase I is then used to conduct Phase II studies in which biological effect is tested. The NOX-A12 trial was conducted in Germany with the approval of the Clinical Trial Application by the Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM). The study is evaluating effects in 42 volunteers with the aim of assessing efficacy in patients with multiple myeloma or non-Hodgkin’s lymphoma in a Phase II trial that is planned for mid 2010. The company states that it plans to obtain marketing approval by 2014. Marketing approval for a drug is granted after 2 double blind, placebo controlled, Phase III studies are performed in which the primary endpoints show a statistically significant improvement over placebo.

The choice of multiple myeloma or non-Hodgkin’s lymphoma as conditions for evaluating NOXA-A12 may be due to the high incidence of patients with these conditions who are poor mobilizers. In these conditions, part of the protocols used clinically, involve mobilizing the bone marrow, administration of chemotherapy, and subsequent reintroduction of the bone marrow into the body.

The adult stem cell company Aldagen Inc, from Durham North Carolina announced today that it has filed a registration with the Securities Exchange Commission for an initial public offering with a potential value of $80.5 million. Details regarding price range or shares to be issues were not disclosed.

Aldagen is one of the adult stem cell companies in advanced clinical trials in the United States. The technology that they are developing is based on intellectual property covering the use of a specific enzyme, aldehyde dehydrogenase (ALDH), as a means of selecting stem cells with higher level of potency from adult sources. Although the particular type of stem cells that Aldagen is selecting for are stem cells that make blood, called hematopoietic stem cells, the company’s technology has been shown to select for other stem cells as well.

It’s most advanced program, is ALD-101, a purified cord blood stem cell product for treatment of inherited metabolic diseases in pediatric patients. This is in Phase III clinical trials, which means that the safety (Phase I) has been demonstrated, that preliminary efficacy (Phase II) has been demonstrated, and now what remains to be demonstrated is efficacy of the product in a double blind, placebo controlled study (Phase III). Several metabolic diseases have been successfully treated with stem cells from the cord blood. Conditions such as Krabbe Disease, involve defective biochemical pathways in cells that original from stem cells. By administration of new stem cells that express the correct biochemical and genetic components, the functioning cells end up taking over the function of the nonfunctioning cells.

The company is also preparing to conduct a Phase III clinical trial for critical limb using its product ALD-301. This product involves extraction of patient bone marrow, purification of cells expressing ALDH, and re-administration of the purified cells into the muscles of patients with critical limb ischemia. The rationale for this treatment is that patients with critical limb ischemia lack appropriate circulation in their legs and are at risk of amputation. By administration of the patient’s own stem cells, the cells are believed to stimulate the production of new blood vessels, which theoretically will reduce the need for amputation. Previous studies using stem cells for treatment of critical limb ischemia have demonstrated successful results in terms of improved walking distance and increased circulation (Kawamoto et al. Intramuscular Transplantation of Granulocyte Colony Stimulating Factor-Mobilized CD34-Positive Cells in Patients with Critical Limb Ischemia: A Phase I/IIa, Multi-Center, Single-Blind and Dose-Escalation Clinical Trial. Stem Cells. 2009 Aug 26), to our knowledge, the proposed Phase III trial will be the first FDA registration trial for use of stem cells in critical limb ischemia.

Additionally, Aldagen is developing ALD-201, which uses the patient’s own bone marrow derived stem cells, but instead of administering them into the ischemic leg, they are administered into the heart muscle by means of a specialized catheter. Currently ALD-201 completed a Phase I trial. In contrast to other cardiac clinical trials involving administration of stem cells after a heart attack, this is one of the few trials that is treating patients with chronic heart failure. Essentially the concept is that the stem cells will be able to create new blood vessels, which will help by providing more oxygen to the cardiac muscle, as well as stimulate stem cells that are resident in the heart through the production of various growth factors.

The company is performing several areas of investigation, including purification of cancer stem cells using their technique, as well as expansion into other disease conditions such as stroke and improvement of post-transplant reconstitution.

As with many biotechnology companies, Aldagen is not expected to be profitable in the close future. In the first nine months of 2009 the company spent 9.7 million, while a year ago it spent $13.8 million. The majority shareholder is Intersouth Partners, an early-stage venture capital who invests in companies in the South East US. Intersouth owns 41.6 percent of Aldagen. The underwriters of the IPO are Cowen and Co. and Wells Fargo Securities. A copy of the full S-1 filing may be obtained at the SEC website http://www.sec.gov/Archives/edgar/data/1128188/000119312509215575/ds1.htm

Once again, adult stem cells derived from adipose (fat) tissue are in the news for the therapeutic promise that they offer in the treatment of a number of diseases, especially heart disease.

Dr. Stuart Williams of the University of Louisville and the Cardiovascular Innovation Institute in Kentucky is currently in the process of designing a clinical trial, which he anticipates will commence within 9 months, in which adipose-derived adult stem cells will be tested in the treatment of patients with heart failure. He then realistically believes that an adipose-based adult stem cell therapy will be widely available in the U.S. within 3 to 5 years.

A number of studies have already been completed in which adipose-derived adult stem cells have been tested as a therapy for heart failure, with extremely positive results. Current similar studies are also in the process of being repeated on cardiac patients in Spain.

According to Dr. Keith March, director of the Vascular and Cardiac Center for Adult Stem Cell Therapy at Indiana University, "These sorts of cells are extremely readily available and abundant, and their normal function is tissue repair." As Dr. Williams half-jokinglly adds, "God made love handles for a reason."

Dr. Williams, a recognized pioneer in the field of adipose-derived adult stem cells, was originally inspired to investigate fat cells years ago when he met Dr. Martin Rodbell, a biochemist at NIH (the National Institutes of Health) who had won the Nobel Prize in Physiology or Medicine in 1994. Dr. Rodbell’s research interest at that time had focused on adipose cells from rats, especially those cells that floated to the tops of the test tubes. Dr. Williams, on the other hand, became curious about the denser fat cells that sunk to the bottom, and began to investigate their properties. Willliams was later awarded a U.S. patent for developing a method by which stem cells are isolated from adipose tissue – the same method that is employed today by research specialists in laboratories around the world.

The International Federation for Adipose Therapeutics and Science (IFATS) has estimated that there are approximately 300 scientists in the U.S. today who are studying adipose-derived stem cells, with approximately 10 laboratories that are exclusively focused on the topic.

Although adipose-derived adult stem cells have proven to be highly potent, capable of differentiating into a wide variety of tissue types, a few safety questions still remain unanswered. According to Dr. Yong-Jian Geng, for example, director of cardiac research at the Texas Heart Institute, "The main concern is we don’t want to develop fat tissue in the heart."

Whatever discoveries might ultimately be made regarding the clinical viability of adipose-derived stem cells, the ongoing research and clinical trials are an important part of that discovery process. As Dr. Williams further explains, "It’s like space travel. You do it because it’s there. You do it because it’s science and it’s the unknown."

The Belgian adult stem cell company, Cardio3 BioSciences, today presented an update of its C-Cure adult stem cell therapy for heart failure at the 10th annual conference of the European Society of Cardiology in Barcelona.

Described as a second generation adult stem cell therapy, C-Cure allows the differentiation of a patient’s own (autologous) adult stem cells into "cardiopoietic" cells which then differentiate into new cardiac tissue, thereby repairing heart muscle. The proprietary product is derived from autologous adult stem cells that are harvested from each patient’s own bone marrow and cultured with a patented laboratory technology that yields the new, regenerative cardiopoietic cells. Currently C-Cure is being evaluated for both safety and efficacy in the treatment of heart failure in a double-blind, placebo controlled, randomized, multi-center clinical trial.

The international congress is featuring a number of recent advances in cardiac regenerative therapies, with particular emphasis given to the progress that has been made from first-generation to second-generation products. According to Dr. Christian Homsy, CEO of Cardio3 BioSciences, "The potential of cell therapies for the treatment of heart failure has long been recognized but there have been considerable hurdles to overcome in delivering on the promise. Today’s expert panel was able to provide a thorough review of the advancements in science that have brought about today’s second-generation cell therapies, and to put our product, C-Cure, into context. We believe C-Cure has tremendous potential to realize the promise of regenerative therapies in heart failure, and we look forward to the results of our pivotal trial."

Headquartered in Mont-Saint-Guibert, Belgium and founded in 2007, Cardio3 Biosciences, S.A., describes itself as focusing on "the field of regenerative therapies for the treatment of heart failure." As further described on the company’s website, "C-Cure is a cell therapy based on the usage of autologous stem cells differentiated into cardiac precursors called cardiopoietic cells. This second-generation cell therapy was developed based on research conducted with the Cardiovascular Center of Aalst, Belgium, and the Mayo Clinic of Rochester, Minnesota, USA."

In 2007, Thomas Clegg was diagnosed with dilated cardiomyopathy, a condition in which the left ventricle of the heart becomes abnormally enlarged. At that time, his ejection fraction – a measure of the heart’s efficiency at pumping blood – was around 9 (nine) percent, whereas a normal ejection fraction is considered to be between 50 and 65%, or higher.

As Mr. Clegg describes, "I was one of the lucky ones. I was still working 8 hours a day. Some people who have 30% ejection fractions can’t walk across the room."

One of his physicians, Dr. Kevin Lisman, informed Mr. Clegg that his best option would be a heart transplant. However, precisely because of the fact that Mr. Clegg was still able to work and remain physically mobile throughout the day, he was very low on the list of recipients, since other people who were in worse condition took precendence.

Then, another option was offered to Mr. Clegg: autologous adult stem cell therapy. Mr. Clegg eagerly accepted the option. According to Dr. Brian Bruckner, who conducted the adult stem cell procedure at the Methodist DeBakey Heart and Vascular Center in Houston, "He didn’t really have a lot of options. Injecting cells directly is kind of a novel idea. We know they help, but we’d like to know more about that mechanism." As Mr. Clegg adds, "My wife and I just wanted to see what was going on. At this point, I would have had to get worse to get a transplant."

In an FDA-approved, Phase II, double-blind, placebo-controlled, multi-center clinical trial in which approximately 40 patients throughout the country participated, Mr. Clegg was the first to receive the adult stem cell treatment, which consisted of treating Mr. Clegg with his own (autolgous) adult stem cells that were harvested from his own bone marrow via his hip. After the doctors in Houston removed 50 milliliters of Mr. Clegg’s bone marrow, it was shipped to Aastrom Biosciences in Ann Arbor, Michigan where the adult stem cells were isolated, expanded and returned to Mr. Clegg’s doctors, who administered the cells directly into Mr. Clegg’s heart.

According to Aastrom CEO George Dunbar, "Lifesaving is where we wanted to focus our efforts. It helps with what nature already does with these mixed cell populations."

Now, nine months after receiving the autologous adult stem cell treatment, Mr. Clegg’s ejection fraction has increased to 30%.

Mr. Clegg has nothing but the highest praise for the medical team in Houston, especially his nurses. As he emphatically states, "They’re my guardian angels. What they’re trying to do is back the clock up. I honestly feel like this has added some time."

At 68 years of age, Brent Benson was suffering from heart failure. As a biochemist who previously conducted tests for the Environmental Protection Agency, Benson was no stranger to physiology and medical science. By his own assessment, he says, "I’m essentially dying of heart failure. I was so far down, I had to try."

Now, however, approximately 5 months after receiving autologous adult stem cell therapy, Benson describes himself very differently. "My life is full and busy," he says. "I had lost that prior to this operation."

Autologous (in which the donor and recipient are the same person) adult stem cell therapy is catching on. Increasingly used in the treatment of a wide variety of diseases and injuries throughout the world, the procedure has shown such consistent success in patient improvement that the news finally seems to be spreading.

In Brent Benson’s particular case, he was able to participate in a clinical trial conducted at the University of Utah in Salt Lake City. After his own adult stem cells were extracted from his bone marrow via his hip, the cells were processed in a laboratory and later injected directly into his heart. He received a total of 30 injections, after which time his heart has exhibited considerable improvement, with his ejection fraction – a measure of the heart’s ability to pump blood – increasing from 15% to over 30%. While an ejection fraction between 55 and 70% is considered normal for healthy people, doctors expect Benson’s ejection fraction to continue to improve.

Heart failure is one of the most prevalent of all diseases, especially in developed nations. The American Heart Association estimates that in the U.S. alone there are more than 5.7 million people who live with heart failure, with approximately 670,000 new cases being diagnosed each year.

Dr. James Willerson is president of the Texas Heart Institute in Houston and a principal investigator of a separate clinical trial sponsored by NIH (the National Institutes of Health), also for the study of adult stem cell therapies in the treatment of heart failure. As Dr. Willerson explains, "When you put (adult) stem cells into a heart, some can differentiate to become blood vessels and others to become heart muscle cells." Additionally, Dr. Willerson adds, these types of adult stem cells, which are known as mesenchymal stem cells (MSCs), also contain growth factors and other beneficial "substances that recruit other cells and promote life," which makes the MSCs particularly efficacious as a clinical therapy. According to Dr. Willerson, "I believe we will be able to regenerate the whole heart of a human being with stem cells."

Dr. Douglas Losordo, director of the Program in Cardiovascular Regenerative Medicine at Northwestern University’s Feinberg School of Medicine, is conducting a pilot study in which 10 patients with heart failure are being treated with their own autologous adult stem cells, derived not from their bone marrow but instead from each patient’s own peripheral blood. As enthusiastic as he is about adult stem cell therapy, however, he is quick to point out that the field is not without its challenges. As Dr. Losordo explains, "Even as a wildly optimistic guy, I don’t imagine that anything I do on a single day in the cath lab is going to reverse 30 years of disease."

Similarly, Dr. Amit Patel, director of Cardiovascular Regenerative Medicine at the University of Utah and the leader of the study in which Mr. Benson is participating, believes that patients should not be shy about seeking adult stem cell treatment, but he also encourages them to conduct their own research and find a medical facility with specialists in a wide variety of fields, who can offer other forms of treatment in addition to adult stem cell therapy. According to Dr. Patel, "This is just one component of the entire continuum of heart failure treatment. It’s the sexiest one, but it’s only one component."

In a comment which is regarded by many as being more than just slightly odd, Dr. Patel also adds that, "With any cell-based therapy, there’s such a high placebo effect. There’s so much hype about the potential of stem cells. It’s positive reinforcement." In specific reference to Brent Benson, however, who lives at an altitude of 9,000 feet, Dr. Patel further acknowleges that, "Elevation, that’s the ultimate stress test." The fact that Benson has regained his energy and vigor following his adult stem cell therapy, while residing at such a high elevation, is concrete evidence for the powerful regenerative capacity of adult stem cells, and probably cannot be attributed solely to "the placebo effect". On the other hand, if someone with clinical heart failure can recover to the extent that their ejection fraction improves from 15% to more than 30%, for no other reason than "the placebo effect", then perhaps more attention should be paid to this grossly misunderstood phenomenon, and perhaps pharmaceutical companies might want to begin bottling and marketing "the placebo effect".

Whether inspite of or because of sudden, remarkable improvement in critically ill patients which is often explained as "just the placebo effect", Dr. Losordo adds that patients should not be afraid to pursue adult stem cell treatment, though he acknowledges that some patients have a difficult time knowing where or how to start. As he explains, "In my opinion, most patients are far too shy about picking up a phone and starting a line of inquiry. All the people involved in this stuff at medical centers, we want to help folks out."

In Brent Benson’s particular case, one of his cardiologists told him, "You don’t have a thing to lose. You don’t have much time left." For most people, a prognosis such as this would be enough to cure them of their shyness.

Not only is Benson now able to be physically active, without fatigue, while tending to the fruit trees on his farm and while also working on the deck at his home in Utah, at an eleveation of 9,000 feet, but also, as Benson now asserts, "I’ve gotten my sense of humor back."

Not bad, for "the placebo effect".