In an article published in the August 2007 issue of the Journal of Bone Marrow Transplantation, Dr. Shalini Shenoy reviewed the latest advancements in stem cell transplantation which allow for low toxicity and high success rates in the treatment of sickle cell anemia. However, as Dr. Shenoy pointed out, stem cell therapies are not yet in common use for the treatment of this disease. Today, Dr. Shenoy is now leading one of the largest studies ever to be conducted in the treatment of sickle cell anemia, as this comprehensive clinical trial is designed specifically to test the safety and efficacy of stem cell therapy on a grand scale. As associate professor of pediatrics at the Washington University School of Medicine, and medical director of the pediatric bone marrow transplant program at St. Louis Children’s Hospital, Dr. Shenoy is directing the nationwide, multicenter Phase II clinical trials for the use of adult stem cell therapy in the treatment of children with the most advanced forms of the disease. Qualifying participants will receive stem cells derived either from bone marrow or umbilical cord blood. A total of 45 patients are sought, between the ages of 3 and 16, who suffer from the most severe, most life-threatening forms of sickle cell anemia.

According to Dr. Shenoy, “Right now, blood stem cell transplant is the only potential curative therapy for severe sickle cell disease.” Approximately ten patients with sickle cell anemia improved after receiving stem cell transplants in preliminary trials, the results of which were so positive that interest was generated in expanding the trials to a larger population group.

An inherited blood disorder in which hemoglobin is abnormally shaped, sickle cell anemia afflicts approximately 70,000 people in the U.S. alone, occurring in 1 in every 500 African-American births, and 1 in approximately every 1,200 Hispanic-American births. Previously, blood transfusions and bone marrow transplants have offered the only known treatments, both of which have serious complications which include graft-versus-host disease and a 10% mortality rate from bone marrow transplantation. By contrast, hematopoietic stem cell therapy has been shown to restore normal hematopoiesis to people who are suffering with sickle cell anemia, with very low risks.

The upcoming nationwide trial is supported by the National Marrow Donor Program, the Sickle Cell Disease Clinical Research Network, the Bone Marrow Transplant Clinical Trials Network of the National Heart, Lung and Blood Institute, and the Pediatric Blood and Marrow Transplant Consortium.

Stem cells are known to reside in most types of tissue throughout the adult human body, but until recently it was believed that the heart is one region of the body which does not contain its own stem cells. Such a theory has now been proven to have been erroneous.

A number of recent studies have led to the identification of a small pool of stem cells that reside in the adult human heart, and now researchers in the Netherlands have successfully isolated these stem cells. Upon being cultured, the cells spontaneously developed into mature heart muscle that exhibits rhythmic contraction and is also responsive to electrical stimulation and adrenaline. According to Dr. Pieter Doevendans of the University Medical Centre in Utrecht, “We’ve got complete control of this process, and that’s unique. We’re able to make heart muscle cells in unprecedented quantities, and on top of it they’re all the same. This is good news in terms of treatment, as well as for scientific research and testing of potentially new drugs.”

Cardiac muscle is among the most specialized types of tissue in the body and is typically highly resistant to repair following damage such as that caused by a heart attack or acute injury. For this reason, conventional wisdom held that the heart must be devoid of stem cells, but now that it is known that the heart does in fact contain its own stem cells, further studies will investigate the precise role that such stem cells play in cardiac health and function. With the assistance of modern medical technology, such endogenous cardiac stem cells can ultimately be utilized in the treatment of heart disease and other cardiac problems.

Stromal cells are found in the endometrial lining of the uterus and are shed every month during menstruation. Stromal cells are also found in connective tissues throughout the body, and are known to differentiate into new cartilage, bone, fat, heart, skin and brain cells. Such cells are now the focus of intense research throughout the world, as the discovery of their presence in menstrual blood offers a new opportunity for easily and noninvasively collecting such prized cells. Known as MenSCs (menstrual blood stromal cells), these cells may be harvested from a potentially unlimited, inexpensive, and continuous source by methods that are free of ethical controversies.

According to Dr. Amit Patel, director of Cardiac Cell Therapy at the University of Pittsburgh’s McGowan Institute of Regenerative Medicine, “Uterine stromal cells have similar multipotent markers found in bone marrow stem cells and originate in part from bone marrow.” When the MenSCs were grown in the laboratory, the cells were found to divide very rapidly, even more rapidly than stromal cells that are harvested directly from bone marrow. Although MenSCs do not divide as fast as embryonic stem cells do, MenSCs also do not carry any of the risks that are associated with embryonic stem cells, such as the formation of a particular type of cancerous tumor known as a teratoma.

Cryo-Cell International was a partner in conducting the research. According to Julie Allickson, vice president of laboratory operations, research and development at Cryo-Cell, “The preliminary results are extremely encouraging and support the importance of further study of these cells in several different areas including heart disease, diabetes and neurodegenerative disease.” According to Dr. Dwaine Emerich, a section editor for Cell Transplantation, “These studies are a significant step forward in the development of transplantable stem cells for human diseases because they address major issues including routine and safe cell harvesting of renewable cells that maintain their differentiation capacity and can be scaled for widespread clinical use.”

It is believed that these rapidly dividing MenSCs may be of particular usefulness in those diseases that require organ transplantation. Instead of transplanting an organ that has been donated by someone, scientists will instead be able to grow a new organ, and the other new tissue that is needed, from MenSCs such as these.

These findings with MenSCs offer further substantiating evidence for the potency of endometrial regenerative cells (ERCs), the properties of which were first described by scientists of Medistem Laboratories, who published the first full elucidation of ERCs in the Journal of Translational Medicine in November of 2007 in an article entitled, “Endometrial Regnerative Cells: A Novel Stem Cell Population”. The Medistem scientists were then honored with an award by Biomed Central for the best research article of 2007 in medicine, which was presented at the Royal Society of Medicine in London in March of 2008.

With the hope of growing small blood vessels and restoring circulation in the legs, two patients were the first to be treated by transplanting a purified form of the subjects’ own adult stem cells into the leg muscles. Both patients suffered from severely blocked arteries and faced possible leg amputations. This first U.S. trial of the technique that has worked on laboratory animals was conducted by Northwestern University Feinberg School of Medicine.

“They’re at the end of the therapeutic road and they’re ultimately facing potential amputation,” said Douglas Losordo, M.D., the Eileen M. Foell Professor of Heart Research and principal national investigator for the study. “This is hopefully a way to help them avoid that.”

Losordo is director of the university’s Feinberg Cardiovascular Research Institute and director of cardiovascular regenerative medicine at Northwestern Memorial Hospital.

“The stem cells themselves can assemble into blood vessels,” Losordo said. “They can also secrete growth factors that stimulate and recruit other stem cells to come into the tissue and help with the repair. It’s an amazing biology we’re trying to leverage in these folks.”

The approach has proven to be effective in mice and rats during pre-clinical studies where stem cells were transplanted into the limbs of the animals.

“Based on that, we think it has a good chance of helping humans,” Losordo noted.

“This is a dreadful disease in which the profession has failed to offer much in the way of relief for these patients,” Losordo said. “We’re hoping this will have some impact.”

The trial is being conducted at 20 different sites nationally. The first two patients received their transplants at Northwestern Memorial Hospital.

Wounds that don’t heal, the breakdown of tissue, and gangrene can be the result of severely blocked arteries in the leg and sharply diminished blood flow. More than 100,000 limbs are amputated in the United States due to the painful condition call critical limb ischemia (CLI).

Affecting 1.4 million people, the emerging health problem is serious. By the time they reach the age of 70, and estimated 15 percent of the population will suffer from this disease.

Patients who have exhausted all other medical options including angioplasty, stents and bypass surgery to repair blocked circulation in their legs were the target of the Northwestern-led phase I/IIa study, which will include 75 people with CLI around the country.

Affecting about 10 million people in the United States, critical limb ischemia is the result of advanced peripheral artery disease. In peripheral artery disease, people develop blockages in their arteries and vessels that slow or stop the blood flow to their legs.

The condition is called CLI when they have wounds on their legs or feet that will not heal and pain at rest in their lower legs. If left untreated, CLI can result in a patient having toes, a foot or even a leg amputated.

People begin to experience pain when they walk, then when just sitting, as CLI progresses. Since blood flow decreases when people lie down, the pain is the worst at night. In order to lessen the pain and aid in blood flow, some even sleep in chairs.

“Peripheral artery disease is a big health problem,” Losordo said. “There is an emerging awareness of this disease on public health.”

The risk of developing the condition is elevated by high blood pressure, diabetes, high cholesterol and smoking.

However, Losordo points out that, “some people don’t smoke, have diabetes or high blood pressure and can still have blocked arteries in their legs.”
Losordo uses the subject’s own purified stem cells for the randomized, double blind, placebo-controlled trial. CD34+ stem cell from bone marrow are first released into the blood stream by a stem cell stimulating drug. The patient takes this drug for five days prior to the stem cell extraction. Then, the CD34+ enriched blood is obtained by way of an intravenous line that is inserted into a subject’s vein to collect blood through a machine that removes a population of blood cells. Losordo further selects and enriches the cells to select only CD34+ cells.

In order to treat heart disease, induced pluripotent stem cells or iPS cells will be used in a joint study by two professors from Osaka and Kyoto university.

The joint research will be conducted by Osaka University Professor Yoshiki Sawa, who has treated heart disease using cell sheets created from muscle, and Kyoto University Professor Shinya Yamanaka, who created iPS cells that can develop into various types of cells, such as organ or tissue cells, from ordinary human skin.

Cardiac muscle regeneration treatment is the focus of their research.

Yamanaka will be the leader of a newly established iPS cell research center at Kyoto University. The announcement was made on Tuesday.

Using human thigh muscle, Sawa and his research team created cell sheets last year. The heart function of a patient who was a heart transplant candidate was improved when the cell sheets were attached to an area around the heart.

Sawa hopes to turn iPS cells into cardiac muscle cells since the cell sheets do not change into cardiac muscle. He hopes to apply the new research findings to the treatment.

Sawa said, “I’d like to create new cell sheets from new materials using iPS cells, make the sheets available in many cases and enhance the sheets’ practicality.”

The planned research center will be part of the Institute for Integrated Cell-Material Sciences, a world-class research institution that opened in October in Kyoto University.

Several institutions including Kyoto’s University’s Institute for Frontier Medical Sciences will help staff the center with several part-time teams of researchers. The center will also be comprised of a full-time team of 10 to 20 professors, associate professors, researchers and engineers.

The researchers are aiming to develop a safer method of creating iPS cells while sharing their research results. Studying technologies to turn iPS cells into cells for particular purposes is also on the agenda.

Yamanaka said at a press conference on Tuesday that he hoped the planned center would be a research facility open to researchers around the world covering basic to clinical medicine.

“I’d like to nurture young researchers because iPS research requires 10 to 20 years of effort,” he said.

A private incubation facility in Shimogyo Ward, Kyoto, will temporarily host the center in a research lab at the Kyoto Research Park.

With the intent of guiding Japan back to leadership in the field of biotechnology, the Koizumi government adopted a new strategy six years ago.

This did not mark the first time that a national policy initiative of this type was put into effect. And as the current administration tries to capitalize on an exciting stem cell breakthrough, Japan is on the verge of another.

Leading countries have surpassed Japan since 2002.

Japanese biotech drug development, as a ratio of overall drug development, lagged the US, Britain, France and Germany by about 50 per cent according to a report published last year by The Office of Pharmaceutical Industry Research.

Though it is generalization that doesn’t sit convincingly with the nation’s international scientific patents, or Nobel Prize winners over the past 20 years, the disappointing performance in applied biotechnology is often attributed to Japanese science’s alleged weakness at radical innovation.

However, it goes some way towards explaining the surge of official optimism that has built up behind Shinya Yamanaka’s induced pluripotent stem (iPS) cell research team at Kyoto University’s Institute of Frontier Medicine.

It remains to be demonstrated, however, that ministers and officials understand their contribution to previous shortcomings: ponderous and intrusive forms of regulation and administrative guidance that hobble Japanese scientists in the rapidly moving areas of medical and biological R&D.

In the late 1980’s, because of the countries excellence in science education, a high level of government commitment, and track record of converting research into commercial and clinical innovation, Japan was widely expected to become the dominant nation in the exciting new field of biotechnology even at senior policy levels in the US.

Intense bureaucratic supervision usually accompanies a high level of official commitment to an undertaking in Japan, and this is one reason why the biotechnology revolution did not take off in Japan as predicted.

Stem cell research programs can wait 12 months for government approvals, and once under way, pharmaceutical and biotech companies complain, grant-funded research is inflexibly administered.

Approval procedures are far lengthier than in the US and most other Western countries for new drugs and clinical procedures.

However, a fantastic door to opportunity for Japanese leadership has been opened by iPS cell research.

The Yamanaka team’s work seems to have signposted the path to the summit of biotechnology: stem cell therapy with its enormous promise to treat conditions such as Parkinson’s, diabetes, heart and spinal cord damage – but unencumbered by the ethical difficulty of using cloned human embryos or eggs to create embryonic stem cells.

The use of four genetic “transcription factors” to successfully reprogram mice skin cells into becoming stem cells was announced by Yamanaka in June. Another team from the University of Wisconsin was able to produce human iPS cells in November. Not long after, Yamanaka’s group succeeded in making iPS cells using only three transcription factors.

Since the gene c-myc can often cause tumors, they omitted it from the other four.

National admiration has risen for Yamanaka and the world’s attention as focused on the rush of innovation.

But almost invariably, a glum recitation of previous shortfalls in Japanese biotech comes out of what begins as news of further advances in the science or more government support for developing the technology.

The reason is not difficult to see.

Japan imposes the heaviest regulatory conditions of any country that permits embryonic stem cell research. So it is not difficult to at least partially understand why Yamanaka moved into iPS research.

He has complained about the Government’s “terrible regulations and crazy policies that crush any long-term projects”.

Other aspects of the iPS discovery have reached another breakthrough point said Yamanaka in an interview with Tokyo reports last week. However, stem cell therapy is still years away from clinical application he said.

“The other applications, like toxicology and drug development, it’s ready to go,” he said.

“We can use iPS cells in these applications today, if somebody can pay a lot of money – like pharmaceutical companies.”

Those applications involve using iPS cells to create, for instance, neural cells outside someone’s body so they can be tested for personal disease factors, or for an exactly tailored drug treatment.

An immediate start to

Recent breakthroughs in stem cell research have produced embryonic stem cells from non-controversial adult skin cells. These same scientists are now being funded by a Japanese government agency which has decided to forge ahead with stem cell research.

Human embryos, aborted fetuses, and adult stem cells made up the only three options for stem cell research. But that is no longer the case.

After the scientists reported their amazing discovery of being able to create stem cells from human skin cells, a mere 2 weeks passed before the decision was made by the Japan Science and Technology Agency to release the funds.

Due to the fact that scientists will no longer need to create and destroy an embryo in order to extract stem cells, critics of stem cell research should tone down their protesting due to this discovery.

The cells can be used to treat many different parts of a person’s body depending on their injury or medical disease/condition. The fact that they can be converted into many different types of cell tissue after they are extracted makes the discovery particularly amazing.

The cells were converted to an embryo like state by injecting them with genes. Skin cells from the foreskin of a newborn and normal skin cells from a 36 year old woman’s face were utilized by the Japanese and U.S. research teams. Cartilage, fat, muscle, brain, and heart cells were among those that were created from the skin cells.

In order to determine if the newly programmed stem cells actually are what they appear to be more studies will be required say both research teams.

A shout has been echoing around the world due to the breakthrough.

“We’re on the way now,” said Dr. Michael Creer, director of laboratory medicine at St. Louis University and former director of the St. Louis Cord Blood Bank. “The opportunities are expanding enormously. What we think might work today could well change in the next few months … We still don’t fully understand or appreciate what is possible.”

Many people are jumping up and down with excitement with the possibility of finding treatments and cures for diseases or conditions that currently have limited treatment options. Experts say that the work is far from finished.

“People have to understand that we’re not ‘there’ yet,” said Dr. Steve Teitelbaum, a Washington University pathologist.

Significant treatments have already resulted from stem cell research. Certain eye conditions, cancer, and diabetes are among the conditions which are currently treatable using adult stem cells.