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e-Journal of Age Management Medicine - April 2009

Stem Cell Standards and Guidelines for Clinicians and Labs

Jeff Morris

Within the next 12 months, it's possible that Age Management clinicians will have a new set of tools at their disposal—a whole new way of dealing with the diseases and disabilities of aging that is such a leap from today's medical options, it may well be considered Age Management 2.0. But it's also possible that those options may slip out of the grasp of physicians and become the exclusive purview of the pharmaceutical industry.

Christopher J. Centeno, M.D., is an expert in this area, having spent four years performing an autologous, minimal culture expansion technique in orthopedics that uses adult mesenchymal stem cells. Known as the Regenexx™ procedure, it uses a patient’s own stem cells and blood growth factors to regenerate bone and cartilage. At Regenerative Sciences Inc. (where he also serves as lab director) and CentenoSchultz Clinic in Broomfield, CO (run with Co-Medical Director John R. Schultz, M.D.) the focus is on development of this non-surgical option for people suffering from various orthopedic disorders.

“The cell therapy industry right now is very nascent; it’s where age management was 10 years ago,” says Dr. Centeno. He has established an organization to set up guidelines and standards: The American Stem Cell Therapy Association (ASCTA). “We’re trying to develop physician guidelines in the U.S. for the safe use of stem cells, similar to the way fertility clinics operate,” says Dr. Centeno. “We’ve got an organization to formulate guidelines, and we’ve got clinicians working to form a stem cell registry. But the FDA doesn’t like that. We only do adult cells from the same person, but the FDA contends that if you culture stem cells at all, regardless of the use of those cells, that’s a drug.” He points out that the age management community has seen many instances where the FDA has tried to insert itself into the practice of medicine—where it has been strictly prohibited by congress from treading—and this is just the latest. “Compounding pharmacies have been coming under FDA pressure for a long time, and have now organized and set up their own standards and guidelines as a way to combat that.”

Dr. Centeno compares the current state of stem cell medicine to the history of fertility treatments. “If you’re a fertility specialist, you have to grow that person’s cells at least to the blastocyst stage to use them, and the FDA has no control over that. If the FDA had gained control, you wouldn’t have individual fertility practices—just a few big labs across the country.” Instead of being regulated by the FDA, fertility doctors are regulated state by state. The reason, says Dr. Centeno, is simple: “They organized, put their own standards in place, and created a case, saying, ‘Listen, this is the practice of medicine, and you’re not allowed to regulate the practice of medicine.’”

Prior to becoming involved in stem cell research, Dr. Centeno was already an international expert and specialist in musculoskeletal, spinal, and neurologic injury. Having trained at the Baylor College of Medicine, Texas Medical Center, and the Institute for Rehabilitation Research, he is an M.D. who is double boarded in both Physical Medicine and Rehabilitation as well Pain Medicine. Dr. Centano has seen the results that are achievable in an orthopedic context. “We’ve done this for four years for patients with orthopedic conditions, so as a test case, we know it can work safely and effectively.”

To Dr. Centeno, it is inconceivable that a person’s own cells could be classified as a drug—but that is exactly what the FDA wants to do. “The FDA is working to protect the interests of Big Pharma,” he says. “If we wanted to insert some kind of new genes into these cells, we’d all agree that would be a drug—a new entity. But this is simply culturing a person’s own cells. Most of the cells are bone marrow derived; you can get them from synovial fluid in the knee and other sources.” There are three main types of adult stem cells:

-Mesenchymal stem cells are commonly found in the bone marrow.  These cells can differentiate into multiple orthopedic, neural, organ, and other lineages.

-Very Small Embryonic Like Cells (VSEL) are a newer stem cell line with more likely ability to differentiate into multiple cell types and lineages.

-CD34+ heme progenitors are usually derived from bone marrow and can be mobilized into the bloodstream. They have been used commonly in vascular and heart applications.

Most importantly, the mesenchymal cell line alone—the one Regenexx has been using—has more than 8,000 peer-reviewed references showing its wide application in age management medicine, including the treatment not just of orthopedic conditions, but of type II diabetes, stroke, and cardiovascular disease. “It can be used to treat everything from cardiac disease after a heart attack, to vascular disease, to orthopedic injuries,” notes Dr. Centeno. As we move beyond “regenerative medicine 1.0”—which is where Dr. Centeno sees things currently—“I suspect what will happen in 2.0, is that you’ll see some age management medicine doctors start their own regenerative stem cell lab, take cells from that patient, minimally culture them, and then they can be deployed.” For instance, in cases of diabetes, the cultured cells would be injected under CT or ultrasound guidance directly into the pancreas—where, says Dr. Centeno, “in animal models they routinely get rid of diabetes.”

It is important to note that while the recently lifted ban on embryonic stem cell research has helped to bring attention to the whole subject of stem cell-based therapies, the work that ASCTA does is related entirely to adult stem cells, and the patient’s own stem cells at that. “A large number of diseases have already been looked at,” notes Dr. Centeno; “the basic research is already in place.” Some of the areas in which there is ongoing research on the use of adult stem cells in disease treatment, as presented in a “list-in-progress” on the ASCTA website, clearly overlap with areas of embryonic stem cell research:

-ALS-Lou Gehrig's Disease
-Alzheimer's Disease
-Multiple Sclerosis
-Muscular Dystrophy
-Osteoarthritis
-Rheumatoid Arthritis
-Spinal Cord Injury
-Stroke

In terms of treating age-related conditions, Dr. Centeno sees stem cell therapies as an entirely new generation of medicine. “In 1.0 we use hormones,” he explains. “Treating using hormones is great, but at some point the parts wear out—and that’s where 2.0 comes in.” As an example, Dr. Centeno cites a study that was just presented at the American College of Cardiology conference in Orlando, FL, showing a dose response relationship on repairing the heart after acute myocardial infarction, with improved heart function after stem cell injection. As reported on March 31st by HealthDay News:

Treating a heart attack with the patients' own bone marrow stem cells boosts blood flow within the heart and may help reduce long-term complications, a new U.S. study finds.

The study included 31 patients who underwent angioplasty and stent placement after a heart attack. Within one week of the attacks, 16 of the patients received infusions of their own bone marrow cells into the coronary artery in which a blockage had caused the event.

The 16 patients received different amounts of bone marrow stem cells -- 5 million, 10 million and 15 million cells. The 15 patients in the control group received standard medication only. All the patients were followed for up to five years.

After three to six months, patients who received higher doses of bone marrow stem cells showed greater improvement in blood flow within the heart than patients who received lower doses and those in the control group, the researchers said.

"This is critical information for future study design -- the more cells a patient receives, the more beneficial effect we see in the heart," principal investigator Dr. Arshed Quyyumi, a professor of medicine at Emory University School of Medicine, said in a news release.

The researchers also found that higher doses of bone marrow stem cells appeared to help cardiac function, as determined by measuring the percentage of blood pumped out with each heartbeat, and by measuring the amount of tissue death due to inadequate blood supply. However, these results were not considered statistically significant, the researchers stressed.

"These results show that treatment with a patient's own bone marrow stem cells has the potential to reduce long-term complications after a heart attack. We are encouraged by these results and are planning to conduct a more extensive study," Quyyumi said.

“Until now there was no way to treat that,” observes Dr. Centeno. “Obviously, if you are a heart specialist or cardiologist this is of big interest to you.”

The key to treatments using a patient’s own stem cells is to gather and bank those cells in advance. “The number available to treat with, goes down with age,” Dr. Centeno points out. “In a 60-year-old person we might get 60,000; we can grow that in a lab to a million, which is enough to treat a condition. It’s what the body does, but the body can’t always get a sufficient number to the right place at the right time. If someone enters your practice at 40, just starting to see the consequences of aging, you would remove those cells and freeze them.” Though this sounds relatively simple, the prospects for such treatments in the future rest squarely on developing industry standards in the near future. “There are already companies doing that stem cell freezing,” Dr. Centeno notes. “The problem is if the FDA has its way, nobody will be able to use those cells because they will be considered a drug. You won’t be able to use them in any meaningful way; you must incubate them to get them out of the cryogenic state because it’s a delicate process”—and that’s what the FDA considers turning the cells into a drug.

Thus, while development of stem cell standards and guidelines is a work in progress, it is one about which there is a real sense of urgency. “All of this could be done within the next 12 months; we could have hundreds of people across the country doing this work under the ASCTA,” explains Dr. Centeno. “We could get out of the starting gate very quickly if everyone gets on board—but if not, the window’s shut and it’s never going to happen.” The stakes for the pharmaceutical industry are obviously high. “You’re talking about replacing $60 billion in drug and device care with $6 billion in stem cell care,” Dr. Centeno observes. The end result will either be individual physicians owning and controlling labs, or, says Dr. Centeno, “It will all be controlled by Big Pharma, and innovation will move at a snail’s pace.”

Standards that must be derived include these, as enumerated in ASCTA’s Mission Statement:

•    To maximize patient outcomes by producing guidelines for the use of autologous adult stem cells (A-ASC) in medicine
•    To provide standards for minimal culture expansion of A-ASC’s  and their re-implantation
•    To establish that when A-ASCs are minimally culture expanded, are not biologic drugs but rather human tissue.
•    To assert that the minimal culture expansion of A-ASCs is a medical procedure.

Additionally, ASCTA intends to provide standards that are specifically lab and practice oriented:

ASCTA Lab Standards

The ASCTA will assemble member panels to define standards of lab practice for the minimal culture of A-ASCs. Lab standard recommendations will be ratified by a majority of the membership of the ASCTA prior to adoption and publication.

Labs will be inspected and held to best practice standards. Outside partnerships with lab accreditation organizations will be explored. Basic standards will fall into the following categories:

·        Infection and Cross Contamination Control
·        QA Sampling
·        Phenotyping
·        Time in culture standards

ASCTA Practice Standards

The ASCTA will assemble member panels to define standards of clinical practice for therapy involving the harvesting, minimal expansion of, and re-implantation of A-ASCs. Practice standard recommendations will be ratified by a majority of the membership of the ASCTP prior to adoption and publication.
L. Stephen Coles, M.D., Ph.D., Co-Founder of the Los Angeles Gerontology Research Group, has also taken a keen interest in pursuing adult stem cell research for clinical age management, and has spoken with Dr. Centeno about the need to establish standards and guidelines. One of Dr. Coles' concerns is  working with animal models to provide the safety component of a preclinical trial. Dr. Centeno told him, "We have worked with three types of animal models: rats, dogs, and pigs, to demonstrate the safety of 
autologous mesenchymal stem cells infused into the lumbar spine, so we know that they are safe for these animals." 
Furthermore, says Dr. Coles, veterinarians have been using these methods to treat expensive race horses with arthritis or inflamed 
ligaments, to good effect; he cites Vet-Stem Regenerative Veterinary Medicine of Poway, CA [www.vet-stem.com]. Nevertheless, both doctors agree there is no substitute for human studies as 
compared with animal models for human treatment. "Each species presents unique problems in terms of calculating 
the dose of cells, route of administration, and establishing the optimal time for treatment-onset following trauma or
 a chronic condition," noted Dr. Centeno. "Calculating the treatment regimen over several months is also species specific. We hope to 
establish our guidelines in collaboration with a community of stem-cell physicians who are working in this area."


According to Dr. Coles, one of the surprises he found that was counterintuitive in all of this work, is that "if you do it (the stem cell injection) too quickly (after the injury), it doesn’t work; if you wait a week, it works.  Also, if you add too many cells, they don’t help." Dr. Coles can only speculate that the body's own healing process needs to begin, with the stem cells then able to accelerate it—but the exact quantities of stem cells required will only be discovered through trial and error. "
A lot of experiments are needed," he concludes, adding, "Animal models are important; they give us a clue about what we should be trying in humans. But many human trials will be needed."

Overall, Dr. Coles is excited about the near-term prospects for stem cell therapies, even if the amount of work needing to be done is daunting. "There are many new sets of techniques being developed," he points out. "We’re on the cusp of learning a great deal about techniques, and we get blindsided by surprises. We have to learn a lot at the molecular level. What is the atmosphere, what is the proper culture, what are the nutritional requirements for incubating the cells? This is an exciting time; we have an awful ot of work to do to get the answers; people are dying because we don’t know the answers to these questions. We could have a whole new set of treatments within five years—unless the FDA gets involved."

The American Stem Cell Therapy Association is at www.stemcelldocs.org, with links to the latest available research. Dr. Centano urges physicians who are interested in the possibilities for Age Management Medicine to sign up. “Guidelines will be posted open source on the Web,” he says. “Just get online, join, and start creating tasks.”
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