Bioheart announced today that it has received U.S. FDA approval to begin testing it proprietary adult stem cell product, MyoCell SDF-1, for use in the treatment of heart failure. The Phase I clinical trial has a target enrollment of 15 patients and is scheduled to commence later this year.

MyoCell SDF-1 contains autologous (in which the donor and recipient are the same person) adult myogenic stem cells that are derived from each patient’s own thigh muscle and which are then genetically modified to produce specific growth factors (such as the cytokine known as stromal cell-derived factor-1) which are involved in the regeneration of muscle tissue. According to Howard Leonhardt, chairman and CEO of Bioheart, "To our knowledge, this will be the first clinical trial ever to test a combination gene and stem cell therapy for cardiovascular disease."

Headquartered in Florida and founded in 1999, Bioheart is focused on the development and commercialization of autologous adult stem cell therapies for the treatment of chronic and acute heart damage. As described on their website, "Our lead product candidate is MyoCell, an innovative clinical therapy designed to populate regions of scar tissue within a patient’s heart with autologous muscle cells, or cells from the patient’s body, for the purpose of improving cardiac function in chronic heart failure patients. The core technology used in MyoCell has been the subject of human clinical trials conducted over the last six years involving 95 enrollees and 76 treated patients. Our most recent clinical trials of MyoCell include the SEISMIC Trial, a completed 40-patient, randomized, multicenter, controlled, Phase II-a study conducted in Europe and the MYOHEART Trial, a completed 20-patient, multicenter, Phase I dose-escalation trial conducted in the United States."

Additionally, Bioheart has also been cleared by the U.S. FDA to proceed with its "MARVEL Trial" – a 330-patient, multicenter Phase II/III trial of MyoCell to be conducted in North America and Europe. Additional products in Bioheart’s pipeline include multiple candidates for the treatment of heart damage such as the Bioheart Acute Cell Therapy, a proprietary formulation of autologous adult stem cells derived from adipose tissue.

Scientists have discovered a new method for stimulating endogenous heart stem cells to heal damaged heart tissue. Although the study was conducted in an animal model, the results of the study have direct applications to the treatment of various heart conditions in humans.

Led by Dr. Bernhard Kuhn of Harvard Medical School, researchers at Children’s Hospital in Boston have found that the protein neuregulin1 (NRG1) can be used to stimulate endogenous heart stem cells to re-enter the cell cycle, thereby allowing the stem cells to regenerate new heart tissue.

As Dr. Kuhn explains, "To my knowledge, this is the first regenerative therapy that may be applicable in a systemic way. In principle, there is nothing to preclude this going into the clinic. Based on all the information we have, this is a promising candidate."

For example, Dr. Kuhn and his colleagues surmise that someday it might be a routine protocol for patients to receive daily infusions of NRG1 over a period of weeks. As Dr. Kuhn adds, "Contemporary heart failure treatment is directed at making the remaining cardiomyocytes function better, and improvements in outcomes are harder and harder to achieve because these therapies have become so good. But despite this, heart failure is still a fatal disease. Therapies that replace lost heart muscle cells have the potential to advance the field."

Adult stem cells are already known to reside in a number of various tissue types throughout the human body, and they are suspected of residing in all tissue types. Although an endogenous heart stem cell has been identified and is known to exist, it does not exist in large numbers throughout the heart and is therefore not usually sufficient, in and of itself, to repair damaged heart tissue following an acute event such as a heart attack. A number of studies have examined various ways of stimulating other types of stem cells that are not found in the heart to differentiate into new heart cells, but Dr. Kuhn’s study is unique in that it has demonstrated a novel approach to stimulating the endogenous heart stem cells that are already in the heart to regenerate the heart’s own tissue.

In the study, the scientists treated mice with daily injections of NRG1, beginning at one week following the laboratory-induced injury. Within 12 weeks, the mice not only exhibited improved heart function, but they were also found to have an increased number of resident heart muscle cells as well as a reduction in heart muscle scar tissue. As Dr. Kuhn explains, "Most of the related cell death had already occurred. When we began the injections, we saw replacement of a significant number of cardiomyocytes resulting in significant structural and functional improvements in the heart muscle."

In 2007 the the same team of scientists reported that the protein periostin – which is found in developing fetal heart and injured skeletal muscles – also induces cardiomyocyte production and improved heart function in rats. Instead of being injected, however, the periostin was administered via patches that were placed directly on the heart tissue. In light of this current, new study, further trials are now proposed in which periostin and NRG1 could be used together as a combined therapy. According to Dr. Kuhn, "During initial treatment, patients might receive neuregulin injections, and once they are stable and out of the ICU they might be taken to the cath lab for a periostin patch."

According to Duke University cardiologist Dr. Richard C. Becker, who is also a spokesman for the American Heart Association, "This is something that I suspect people in the field of cardiology will be very excited about, and I suspect this interest will stimulate additional research."

Scientists at the New Zealand company Living Cell Technologies have begun clinical trials today in which cells from newborn pigs will be used for the treatment of Type 1 diabetes. Specifically, the transplanted cells will consist of the beta islet cells from the pancreas, which are the cells that produce insulin. The experimental procedure will be tested on eight human volunteers.

A number of other scientists have expressed concern over the trials, however, pointing out that it’s too early to begin testing on humans since no preclinical animal studies were conducted. Among other risks, scientists caution that any of the numerous viruses that are endemic to pigs could "jump species" and infect the humans, therefore not only causing illness in the 8 volunteers but also potentially triggering a new retroviral pandemic.

The medical director of Living Cell Technologies, Dr. Bob Elliott, however, insists that "there is no evidence of a risk." He describes the piglets that have been selected for the study as having been recovered from 150 years of isolation on islands south of New Zealand, and therefore carry no known infectious agents. It is the unknown infectious agents, however, which have other scientists concerned.

According to Dr. Martin Wilkinson, a past chairman of the New Zealand Bioethics Council, the pig cells pose "a very small risk, low enough to be managed in human recipients. There is no conclusion that it should be banned just because of the possibility of risk." There are many other scientists who disagree, however.

Dr. Elliott has conducted two previous human clinical trials of this nature, the first with 6 patients in New Zealand in 1995 and 1996, and the other with 10 patients in Russia which began in 2007. According to Dr. Elliott, some of the subjects responded with increased insulin production, while in other subjects the implanted cells stopped producing insulin after a year, and there were still other subjects whose bodies rejected the pig cells. None of the human trials were preceded by preclinical animal studies, nor has any scientific paper been published on any of these human trials, although Dr. Elliott says that a paper is scheduled for release by the end of 2009.

Such news represents the opposite extreme of that which most countries face. At the opposite end of the spectrum from the U.S. FDA regulatory regime is a total absence of regulatory oversight. While Phase I, Phase II, and Phase III clinical trials in the U.S. typically require a decade or more of human clinical testing – and must always, without exception, be preceded by successful preclinical trials on animals – the opposite extreme is a country in which preclinical animal trials are not required at all prior to testing on humans. In the first case, patients can grow old and die while waiting around for government approval of a scientifically legitimate clinical therapy; while in the second case, patients can die young as a direct result of the experimental therapy which they have volunteered to receive. Clearly, the issue of exactly how federal government regulatory agencies should adapt their laws to keep pace with medical science is a global problem that is in urgent need of being addressed.

For New Zealand in particular, it seems as though a number of regulatory policy issues remain to be resolved. Previous attempts to form a joint oversight agency with Australia – which would have been known as the Australia New Zealand Therapeutic Products Authority – were indefinitely suspended in July of 2007 when the New Zealand State Services Minister, Annette King, announced at that time that, "The government is not proceeding at this stage with legislation that would have enabled the establishment of a joint agency with Australia to regulate therapeutic products. The (New Zealand) Government does not have the numbers in Parliament to put in place a sensible, acceptable compromise that would satisfy all parties at this time. The Australian Government has been informed of the situation and agrees that suspending negotiations on the joint authority is a sensible course of action."

At the very least, it would seem appropriate to establish some sort of regulatory oversight which requires proof of safety and efficacy in preclinical animal studies before allowing human clinical trials to commence, in which human patients unwittingly become the very first guinea pigs on whom a new and experimental procedure is tested.

Additionally, it would also seem as though the 8 individuals in New Zealand who have volunteered for the experimental pig cell therapy are unaware of other clinical trials which have already been conducted elsewhere throughout the world, and which have utilized adult stem cells from humans, not from animals, in the treatment of human Type 1 diabetes.

For example, it has been demonstrated a number of times that when mesenchymal stem cells (MSCs) are administered to mice whose beta cells have been damaged by the administration of the toxic compound streptozoicin, the MSCs increase insulin production in the mice. The use of adult stem cells to induce islet regeneration is also currently undergoing U.S. FDA-approved clinical trials at the University of Miami. The possibility of stimulating islet regeneration does not necessarily depend on differentiation of the adult stem cells into new islet cells but may also occur through the production of growth factors made by the stem cells and which allow endogenous pancreatic stem cells to start proliferating, thereby healing the injured area. For example, from a mouse study in which chemically-labeled bone marrow-derived MSCs were administered to mice with injured beta cells, the MSCs were actually found to stimulate the islet-activating pancreatic duct stem cell proliferation. The possibility of stimulating endogenous pancreatic duct stem cells by pharmacological means is currently under investigation by the company Novo Nordisk, who has administered a combination of EGF and gastrin to diabetic patients in Phase II clinical trials. However, given that adult stem cells produce a "symphony of growth factors" in addition to gastrin and EGF, the administration of adult stem cells seems to possess a higher possibility of success. Both from the ability of MSCs to differentiate directly into pancreatic cells as well as by their ability to activate endogenous pancreatic stem cells, from preclinical as well as clinical data available throughout the world, there is strong evidence to indicate that MSCs are therapeutic for the restoration of insulin production in the treatment of diabetes.

Furthermore, it is also known that adult stem cell therapy can at least ameliorate and in some cases even reverse the secondary pathologies that are associated with diabetes, such as the variety of complications that result from uncontrolled blood glucose levels such as peripheral vascular disease, neuropathic pain and the dysfunction of various organs such as renal failure. Peripheral vascular disease, for example, is caused by endothelial dysfunction, but it is also known that there is a constant migration of endothelial progenitors from bone marrow sources to the periphery. This migration can be measured through the quantification of the content of endothelial progenitor cells in peripheral blood, and in this manner it has been observed that patients who are diabetic and who have higher levels of circulating endothelial progenitors usually have a lower risk of coronary artery disease. The administration of adult stem cells is also known to rejuvenate old or dysfunctional endothelial cells and to increase responsiveness to vasoactive stimuli. On the other hand, neuropathy, which is a major cause of persistent, chronic pain in diabetic patients, has been reversed in patients who were treated with various adult stem cell populations. This was further documented in highly defined animal models of pain in which bone marrow stem cell administration was found to accelerate nerve healing and to reduce chronic pain. The ability of stem cells to naturally repair injured organs has similarly been described for the heart, the liver and the kidneys. Mechanistically, injured organs transmit elaborate chemical signals, such as SDF-1, which attract stem cells and induce cellular differentiation of the required tissue. Accordingly, based upon evidence such as this, adult stem cell therapy also offers the ideal treatment of secondary complications associated with diabetes.

Additionally, adult stem cells inhibit the mediators that cause insulin resistance. As previously described, one of these mediators which causes the body to resist insulin is known as TNF-alpha (tumor necrosis factor alpha). It has been demonstrated that patients with type II diabetes have abnormally high levels of TNF-alpha, and it is also known that the amount of TNF-alpha in the plasma has been shown to correlate with extensive insulin resistance. In other words, the more TNF alpha that is in a person’s blood plasma, the greater is that person’s insulin resistance. MSCs have been found to shut down TNF-alpha production, thereby shutting off inflammation. A number of studies have documented this fact, one of which was published by Aggarwal et al., in 2005 in the journal Blood, entitled, "Human mesenchymal stem cells modulate allogeneic immune cell response." So there is a great deal of evidence documenting the ability of MSCs to correct the body’s resistance to insulin, with applications to Type I as well as Type II diabetes.

Many studies have also demonstrated that adult stem cells can actually become pancreatic-like stem cells. One such study, conducted by Sun et al., was published in 2007 in the Chin Med J., entitled, "Differentiation of bone marrow-derived mesenchymal stem cells from diabetic patients into insulin-producing cells in vitro." In this and other similar studies it was demonstrated that stem cells derived from bone marrow can produce insulin in vitro after a "glucose challenge", in which glucose is given to MSCs that have been treated to become similar to pancreatic cells. The results consistently indicate that the MSCs are in fact becoming cells which produce insulin in response to the glucose in vitro, and a number of studies also exist in vivo. One such study was conducted by Lee et al., and published in 2006 in the Proceedings of the National Academies of Science, entitled, "Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice." In this study, the investigators used the streptozoacin toxin to kill the beta cells in the pancreas of mice, and when MSCs were administered to the mice, insulin production was shown to increase. Another study was conducted by Tang et al., and published in the journal Diabetes, entitled, "In vivo and in vitro characterization of insulin-producing cells obtained from murine bone marrow." In this study, the investigators took stem cells from bone marrow, cultured them, and made cells that appeared to be the beta islet cells. Specifically, the scientists took MSCs, cultured them in glucose and added nicotinamide (the amide part of nicotinic acid, also known as vitamin B3), which is an agent that is known to assist in pancreatic regeneration. The result was the formation of a group of cells that look and behave like pancreatic beta islet cells. The phenotypic expression of these cells does not include CD34 or CD45, therefore these cells are not hematopoietic, but their genotypic expression includes genes that are specific to the pancreas, such as PDX-1, insulin, glucose transporters, etc., so these cells would appear to resemble pancreatic beta islet cells in behavior and function.

Additionally, a group of scientists in Argentina reported in 2007 that 85% of Type II diabetic patients who were treated with their own MSCs were able to stop using insulin. In this technique, stem cells were administered to each patient via a catheter which is directed through the endovascular arteries directly to the pancreatic parenchyma. The catheterization is employed via an arterial route since arteries deliver oxygenated blood to the organs of the body. The catheter is inserted through a puncture in the groin under local anesthesia, and no stitches are required. More than 70 cases of diabetes have been treated according to this technique, with some of these patients having had diabetes for as long as 30 years, and with many of them exhibiting minimal response to conventional treatment. After receiving treatment by this procedure, 90% of these patients have exhibited significant progress which has even led to the complete withdrawal of original medication in these instances. No complications have been seen in any of the patients, even 9 months after treatment. Similar techniques at other laboratories for the treatment of type II diabetes use the patient’s own stem cells which are derived from the patient’s own bone marrow. These bone marrow-derived stem cells are extracted from the patient’s hip and are then separated and expanded in the laboratory, after which time they are injected back into the patient through an arterial catheter in the groin with the use of local anesthesia, as described above.

It is therefore now known that MSCs can correct the two underlying mechanisms of diabetes, namely, the progression of insulin resistance and pancreatic cell death. In regard to the secondary complications, specifically, peripheral neuropathy and neuropathic pain, numerous case reports have documented the neurogenerative abilities of stem cells, and many animal studies have proven that stem cells can prevent neuropathic pain through a direct analgesic effect. One such study was conducted by Klass et al., and published in 2007 in the journal Anesth. Analg., entitled "Intravenous mononuclear marrow cells reverse neuropathic pain from experimental mononeuropathy." Many other clinical reports have also supported the fact that adult stem cells can help regenerate neurons. Similarly, in peripheral artery disease, endothelial dysfunction often results because patients with type II diabetes have low concentrations of circulating endothelial progenitor cells, which are the cells that make new endothelium. Circulating endothelial cells correlate with vascular health, and bone marrow stem cells are rich in endothelial precursor cells. The administration of bone marrow stem cells can therefore improve endothelial health by increasing vascular endothelial function. Another major complication of type II diabetes is kidney failure. This topic was addressed in the same study cited above, conducted by Lee et al., and published in 2006 in the Proceedings of the National Academies of Science, entitled, "Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice." In this study, the mice had been induced to become diabetic through streptozoacin, and the kidneys were examined for inflammatory macrophage infiltration. As with pancreatic tissue, the stem cells were found to home-in on and repair the damaged renal tissue.

Type II diabetes is becoming an increasingly common problem throughout the world, especially in industrialized nations. Although type I diabetes is not as common as type II diabetes, clinical studies have also shown success in treating type I diabetes with adult stem cells. In a study conducted in 2007 by J.C. Voltarelli of Brazil, fourteen patients with type I diabetes were treated with autologous bone marrow stem cells that had been mobilized into the peripheral blood circulation from which they were collected. During follow-up procedures that were conducted between 7 and 36 months, all fourteen of the patients were able to discontinue insulin use.

Adult stem cell therapy has therefore already been described numerous times throughout the medical literature as the first therapy for both type I and type II diabetes which not only alleviates the symptoms of diabetes but also actually reverses the progression of the disease by regenerating damaged tissue and restoring insulin production.

(Please see the related subsection on this website, entitled "Diabetes", listed in the "Research" section).

Physicians at the University of Louisville in Kentucky have announced the successful completion of the world’s first cardiac stem cell infusion.

The patient, 66-year-old Michael Jones, had suffered the first of two heart attacks slightly over 4 years ago, and within 4 months of the second heart attack he was diagnosed with heart failure and permanent scarring of his heart as a result of multiple blocked arteries. Because he had not yet had bypass surgery, he was a good candidate for adult stem cell therapy. In March of this year he underwent bypass surgery for his blocked arteries, during which time Dr. Mark Slaughter, chief of cardiothoracic surgery at the University of Louisville and director of the Heart Transplant and Mechanical Assist Device Program at Jewish Hospital, removed a portion of tissue from the upper chamber of his heart. The tissue was then sent to Harvard University and Brigham and Women’s Hospital in Boston, where the endogenous cardiac stem cells were isolated, expanded and returned to Louisville where doctors injected the cells directly into the scar tissue of the heart via a minimally invasive catheterization procedure that was performed on July 17. Dr. Roberto Bolli, director of the Institute for Molecular Cardiology at the University of Louisville and distinguished chair in cardiology at the Jewish Hospital Heart and Lung Institute, led the study.

Before undergoing the autologous adult stem cell therapy, Mr. Jones had a left ventricular ejection fraction (LVEF) – a measure of the efficiency with which blood is pumped out of the heart’s left ventricle – that was lower than 25% but which is now around 30% and continues to increase. An LVEF of approximately 58% or higher is considered normal for healthy people.

Thus far, fourteen patients have been enrolled in the FDA-approved Phase I clinical trial which has a target enrollment of 20 patients. A second patient underwent the procedure on Friday, July 24.

According to James Ramsey, president of the University of Louisville, "It is an important, historic announcement. The number one killer is heart disease, and we in Kentucky have a higher incidence than the national average." Indeed, heart failure afflicts approximately 6 million Americans throughout the U.S. although the rate is unusually high in Kentucky, where as many as 14,000 deaths per year – in a state with a population of approximately 4 million people – are attributed to cardiovascular conditions, according to the American Heart Association.

As Michael Jones himself stated at a press conference today, "I am very, very grateful and honored to be chosen as the first recipient. This really seemed natural. It just made sense to use the body to regenerate itself." Looking physically well, strong, and fully recovered from the pioneering procedure that he underwent just a few days ago, he also added, "I hope to have as normal a life as anyone. I might even start jogging again."

According to Dr. Steve Duncan, professor of human and molecular genetics at the Medical College of Wisconsin, the failure of the new NIH Guidelines to "grandfather" in the already existing hESC lines has had a "tremendously detrimental effect on our research."

As Dr. Duncan explains, "The problem is they haven’t added the presidential lines as a group of lines that we can now use. So we can’t do any human embryonic stem cell (hESC) research with new federal funds at this point. We’re hoping within the next two months that it will be relaxed, but that’s a long time in research and it’s reallly upsetting, the way it’s been handled."

Once again, as previously reported a number of times on this website, at the heart of the debate are the "voluntary and informed consent" rules which are contained within the new NIH Guidelines. Many, if not all, of the hESC lines that already exist were created before such rules of consent were authored, and therefore do not meet "the core ethical principles and procedures" that are defined in the new NIH Guidelines. Even though NIH says that such hESCs are subject to review by an advisory committee and might therefore be "grandfathered" in, there is still widespread doubt among the ESC scientific community that many of those lines will be approved for the federal funding of research.

In fact, contrary to popular opinion, there is one major obstacle in the U.S. which is preventing stem cell therapies from being available in clinics at this very moment, and that obstacle has nothing to do with NIH nor with embryonic stem cells nor with any restrictions that the Bush administration supposedly imposed nor with any restrictions that the Obama administration supposedly lifted. Instead, that one, single, primary obstacle is the fact that the U.S. FDA (Food and Drug Administration) has decreed that autologus (in which the donor and recipient are the same person) adult stem cells are a "drug", and therefore must be regulated as such, and therefore cannot be used for therapeutic purposes in the U.S. without having first been subjected to the lengthy, lethargic, outdated, multi-year, multi-million dollar federal governmental approval process, in the same manner as which pharmaceutically manufactured drugs are regulated. Such a stance is without any scientific basis whatsoever, and a number of individuals and organizations are attempting to initiate a much-needed and long-overdue reform of the FDA on this issue. Until the FDA is completely overhauled, however, it seems as though U.S. academicians will continue to focus all of their time and attention on arguing over the federal funding of embryonic stem cell research while apparently remaining oblivious to the fact that doctors and patients are not willing to sit around and wait another decade for something to happen, but instead are traveling overseas where adult stem cell therapies are already available in clinics in just about every country in the world except the United States. (Please see the related news articles on this website, entitled, "Arizona Man Travels to Central America for Adult Stem Cell Therapy", dated July 16, 2009; "Bangor Family Heads to Central America for Adult Stem Cell Therapy", dated July 8, 2009; "Texas Woman Travels to Central America for Adult Stem Cell Treatment", dated June 25, 2009, and "Two U.S. Adult Stem Cell Companies Form Collaboration in Asia", dated May 11, 2009).

Despite all the exaggerated hype over embryonic stem cells, usually at the complete exclusion of adult stem cells, Dr. Duncan nevertheless predicts that future stem cell research will shift more toward adult rather than embryonic stem cells, and not just for the numerous sound scientific and medical reasons but also for ethical reasons as well. Despite his own interest in hESC research at the moment, he also pointed out that, "I think we have to take into account the ethical situation."