Crohn's Disease Stem Cell Treatment, Research, Transplant, Therapy, Information   

Stem Cell Clinics
Patient Application
FAQ
Contact
Locations
Our Scientific Articles
News
Videos
Research
Alzheimer's Disease
Crohn's Disease
Diabetes
Heart Attack Damage
Multiple Sclerosis
Muscular Dystrophy
Osteoarthritis
Parkinson's Disease
Rheumatoid Arthritis
Spinal Cord Injuries
Stroke
Systemic Lupus
Traumatic Brain Injury
Stem Cell Primer
Introduction
What are Stem Cells?
Bank Account Analogy
Key Terms
Types of Stem Cells
Types Compared
History
Regulation
Therapeutic Cloning
Successful Treatments
Regeneration
Conclusions
Glossary
Bibliography
FAQ
Patents
3D Culture/Scaffold
Administration
Differentiation
Expansion
Extraction/Preservation
Mobilization
Type
USE
 


Crohn's Disease Treatment with Stem Cells

Stem cell treatment offers an alternative to conventional therapies for Crohn's Disease which consist solely of drugs that suppress inflammation, drugs that suppress the immune system, antibiotics and surgery.

In Crohn's disease there are two primary areas of the human body which need to be repaired, namely, damaged intestinal tissue and the immune system. Normally, in healthy people, whenever injury or assault is incurred, the immune system contributes in a swift and appropriate manner to the healing process. In Crohn's disease, however, the immune system has malfunctioned and an uncontrolled immune response propagates itself in an escalating fashion. A logical treatment for Crohn's disease would therefore consist of a therapeutic modality which would simultaneously repair damaged intestinal tissue while also correcting immunological abnormalities.

Stem cell therapy accomplishes both tasks.

Stem cells are naturally present throughout the intestine, and targeted therapies are being developed that would stimulate the regenerative capacities of these stem cells that already exist in the regions surrounding the tissue that is damaged from Crohn's disease.

Stem cells do, in fact, exist throughout the body, throughout life, from conception through adulthood, throughout all species. In 2005, researchers at the Howard Hughes Medical Institute outside of Washington, D.C., in collaboration with researchers at Harvard Medical School and the Carnegie Institution of Washington, D.C., successfully identified and isolated stem cells in the intestine of Drosophila melanogaster, more commonly known as the fruit fly. These progenitor cells are capable of differentiating into multiple types of intestinal cells, and research with the Drosophila intestinal stem cells (ISCs) is yielding insights into the mechanisms of a variety of human digestive diseases. According to Dr. Allan Spradling of the Carnegie Institution of Washington, D.C., one of the principal investigators of the study,

"The Drosophila stem cell system is much like the more complicated vertebrate system, but stripped down just to the essentials. So it's much easier to work out the basic biology of what information one cell conveys to another."

According to another principal investigator, Dr. Craig Micchelli,

"Gut stem cells have not been unambiguously identified in mammalian systems, so with the discovery of Drosophila ISCs, we have the first characterization of gut in a tractable molecular system. There are a number of gastrointestinal diseases and cancers whose molecular basis is only poorly understood. The Drosophila system will enable us to rapidly identify the genes that normally regulate self-renewal. Ultimately, we seek to shed light on gastrointestinal disease by understanding the consequences that mutant forms of these genes have on tissue homeostasis."

Findings from their research were published in the journal Nature.

The Drosophila genus, of which Drosophila melanogater is one of the most popular species, is an important research model that is prized for its genetic malleability and which has been extensively studied for over a century, ever since Dr. Thomas Hunt Morgan first began experimenting with mutations in the fly in 1906. His research proved Drosophila melanogaster to be an exemplary organism for studies of genetic heredity since it is easily bred, it has a short natural life span and reproduces quickly so that successive generations may be compared, and it easily acquires genetic mutations which are morphologically visible in adults. Through Drosophila Dr. Morgan was able to identify the role of chromosomes in genetic inheritance, for which he was awarded the Nobel Prize in Physiology or Medicine in 1933. Today Drosophila continues to be ubiquitously employed as a research model in the broad field of molecular biology and in medical applications of biochemistry, cell-biology, genetics, and developmental biology. In 2006, NASA astronauts studied Drosophila melanogater in space in a series of experiments to examine the effects of spaceflight on the immune system. Drosophila is officially classified as a "model organism", meaning that it is studied with the specific expectation that any discoveries will be translatable to applications in other species, especially in the treatment of human diseases, which is scientifically possible due to the principles of conservation of metabolic and developmental pathways and of genetic material among species. Viruses, prokaryotes, eukaryotes, invertebrates and vertebrates are also extensively utilized as "model organisms" toward specific research objectives in the study of human health and disease. As one of the most widely employed research models over the past century, Drosophila has already been well described in genetic detail, and the genome of D. melanogaster was sequenced in the year 2000. Approximately 75% of all known genes that are associated with human diseases have corresponding correlates in the genes of Drosophila, and 50% of all Drosophila protein sequences have mammalian analogues. Drosophila is being studied as a genetic model for a number of human diseases such as diabetes, cancer and immunological disorders, and in the study of many neurodegenerative illnesses such as Alzheimer's, Parkinson's and Huntington's diseases. In the study of digestive diseases such as Crohn's disease, Drosophila surpasses animal models in its genotypic and phenotypic pliability and in the speed at which it yields results.

Animal models continue to generate promising developments as well, however, and in June of 2007, at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, in collaboration with researchers from the Harvard Stem Cell Institute and the University of California at Los Angeles, researchers successfully transformed cells from the skin of mice into pluripotent stem cells that appear to be functionally identical to embryonic stem cells. One of the researchers, Dr. David Scadden, a stem cell biologist at Harvard Medical School, described the accomplishment as "truly extraordinary and frankly something most people assumed would take a decade to work out."

The researchers demonstrated that ordinary adult cells such as a skin cell can be "reprogrammed" with simple biochemical techniques that included, in this particular case, the insertion of 4 genes into a mouse fibroblast skin cell, which cause the cell to revert to a primitive cellular stage that is indistinguishable from that of embryonic stem cells. The technique was originally developed in 2006 by Dr. Shinya Yamanaka at the Kyoto University in Japan, where the method was named "induced pluripotency". Dr. Yamanaka's findings were then successfully reproduced by 2 independent teams, one of which was led by Dr. Rudolf Jaenisch of the Whitehead Institute and the other of which was led by Dr. Kathrin Plath of UCLA and Dr. Konrad Hochedlinger of the Center for Regenerative Medicine at Massachusetts General Hospital and the Harvard Stem Cell Institute. Affiliated with the Massachusetts Institute of Technology (MIT), the Whitehead Institute for Biomedical Research described the findings in a news release entitled, "Reprogrammed fibroblasts identical to embryonic stem cells." According to Dr. Jaenisch,

"These reprogrammed cells, by all criteria that we can apply, are indistinguishable from embryonic stem cells."

Dr. Irving Weissman is the director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine, director of the Stanford Comprehensive Cancer Center, and professor of Pathology, Developmental Biology and Neurosurgery at Stanford University. Although he did not participate in these experiments with the mouse fibroblasts, he is a frequently sought advisor on stem cells and a frequent contributor to the media on the subject. In a statement made to the New York Times, Dr. Weissman declared that,

"From the point of view of moving biomedicine and regenerative medicine faster, this is about as big a deal as you could imagine."

These reprogrammed, induced pluripotent stem (iPS) cells behave in a manner that is functionally equivalent to that of embryonic stem cells, meaning that they exhibit the same pluripotency with which to differentiate into multiple types of body tissue. The technique developed by Dr. Yamanaka poses less technical difficulties than do current procedures for developing human embryonic stem cell (hESC) lines, although it is not yet known whether any of the many problems that are inherent in ESCs would still exist in the iPS cells or not, such as the risk of teratoma (tumor) formation, genetic instability and difficulty in controlling differentiation, all of which are characteristic of ESCs. Assuming that such inherent dangers are not found in the iPS cells, it would, at least theoretically, be possible according to this technique to produce human cell lines that are genetically identical to each patient, thereby avoiding the problem of immune rejection that is also inherent in ESCs.

The next step will be for the researchers to adapt the procedure from mouse to human fibroblasts, and to test the resulting cells for any inherent defects. If the procedure proves to be successful in humans, the technique would have a number of advantages over the use of embryonic stem cells and somatic cell nuclear transfer, also known as "therapeutic cloning." The human iPS cells could then be used in the treatment of a wide range of human diseases, including Crohn's disease.

The findings were first announced in the June 6th, 2007 online issue of the journal Nature.

The reprogramming of a specialized, differentiated cell to a more primitive form is known as de-differentiation (the opposite of differentiation), and experiments with de-differentiation are not new. In 2003, researchers at the Scripps Research Institute in San Diego identified the synthetic molecule reversine as an effective agent which induces cells to de-differentiate, and to revert back to their more primitive, stem-cell-like state. As Dr. Sheng Ding of the Scripps Institute stated in 2003 in regard to reversine,

"This has the potential to make stem cell research more practical. This will allow you to derive stem-like cells from your own mature cells, avoiding the technical and ethical issues associated with embryonic stem cells."

His findings were published in the Journal of the American Chemical Society.

A number of clinical trials have been conducted in the U.S. with Crohn's disease patients who have been treated with stem cell therapy, demonstrating the efficacy, safety and preferability of adult stem cell therapy over conventional Crohn's disease therapies. Some of the most concrete examples of the successful treatment of Crohn's disease patients thus far have involved the use of stem cells that were derived from bone marrow.

One such clinical trial was performed at the Division of Immunotherapy in the Department of Medicine at Northwestern University Medical Center, in conjunction with the Feinberg School of Medicine at Northwestern University in Chicago. Among the participants of the clinical trial was a 13-year-old who was treated at the affiliated Children's Memorial Hospital, and who is the youngest person ever to have received stem cell treatment in the United States. The child had been diagnosed with Crohn's disease at the age of 10 and had since been unresponsive to conventional therapies, having been hospitalized numerous times, often requiring blood transfusions as a result of intestinal bleeding. The child exhibited stunted growth and was taking 33 prescription pills per day prior to enrolling in the clinical trial, which was approved by the child's insurance company and by the federal regulators at the Food and Drug Administration (FDA). The child responded well to the therapy and continues to improve.

Ten people have been treated in this clinical trial and all have improved after receiving the autologous stem cell procedure, which utilizes stem cells that are harvested from the patient's own bone marrow and readministered intravenously.

Another patient was a 16-year-old male who had been diagnosed with Crohn's disease a year earlier, during which time he suffered from constant stomach pain and cramping and the loss of 50 pounds, having been hospitalized 3 times in the course of the year during which he missed 49 days of school. Prior to enrolling in the clinical trial, he had been prescribed a special diet consisting exclusively of liquid supplements and rice cereal, in combination with dozens of pills per day to prevent infection and further pain. As a result of the stem cell treatment he is currently in remission and continues to improve.

Another patient who participated in the clinical trial was a 22-year-old female whose symptoms improved immediately and within ten weeks she entered remission. Having been diagnosed with Crohn's disease at the age of 11, she suffered as many as 10 attacks of painful diarrhea per day and never weighed more than 90 pounds. Additionally, after years of corticosteroid treatment with prednisone she developed osteoporosis. After 2 years of nightly intravenous nutritional therapy, her gastroenterologist recommended her for a colostomy but instead decided to try stem cell therapy. She then participated in the FDA-approved pilot study for non-myeloablative autologous hematopoietic stem cell transplantation, in which she became the first patient to receive this treatment. As a result of the procedure she is enjoying remission for the first time since having been diagnosed with the disease over a decade earlier.

The clinical trial was designated specifically for patients with refractory Crohn's disease, that is, for people with severe cases of the disease who had been unresponsive to corticosteroids, azathioprine, 5-ASA metronidazole, and infliximab. All ten patients who were treated with the stem cell therapy are in remission, many of whom have now been in remission from Crohn's disease for a year or longer. As Dr. Richard Burt, a stem cell transplant specialist and one of the principal investigators at the Medical Center, explains,

"We offer the stem cell transplantation to those who have very serious disease and have failed everything else. The 10 people whom we have treated are all doing great and are in clinical remission."

In all participating patients the efficacy of the treatment was compared to that of standard therapy by the Crohn's disease activity index (CDAI), as well as by a more global severity index known as the Crohn's Severity Index, and by the type and amount of therapy required for the treatment, and by the resultant clinical, hematologic and biochemical studies. Findings have strongly indicated that stem cell treatment is more easily tolerated by the patient and is more efficacious in the treatment of Crohn's disease than are conventional pharmacological therapies.

Adult stem cells have demonstrated such a high rate of success in the treatment of Crohn's disease that a number of proprietary therapies are being developed within the biotech industry in order to capitalize upon this phenomenon. One such example is Osiris Therapeutics, Inc., which has developed a preparation of mesenchymal stem cells (derived from bone marrow) that is specifically formulated for intravenous infusion and which is marketed under the name Prochymal. In January of 2007, the U.S. FDA granted Osiris Therapeutics the "fast track" designation for Prochymal, allowing Phase III clinical trials to commence, which is the final phase of testing before full approval may be granted for the national marketing of Prochymal. According to Dr. Jane Onken, director of the Inflammatory Bowel Disease Clinic and associate professor of medicine at Duke University School of Medicine,

"Prochymal's unique mechanism of action may represent a new class of anti-inflammatory agents. Laboratory data indicate that the stem cells in Prochymal respond according to the level of inflammation present. When there are higher concentrations of inflammatory signals, the cells produce a stronger anti-inflammatory effect. When there is no inflammation, the anti-inflammatory effect is turned off. It is our hope that this proportional response will lead to a treatment that avoids many of the dangerous side effects associated with systemic immunosuppressive therapy, and provide us with a safer alternative for treating patients with serious inflammatory diseases."

The FDA grants a "fast track" authorization only to newly developed potential therapies which show unusual promise in offering an effective treatment for life-threatening conditions. The fast track designation expedites and accelerates the pre-market review process, thereby allowing a more rapid approval of the therapy, assuming that all preconditions are successfully met. Prochymal has also been submitted to the corresponding European and Canadian regulatory agencies for review and approval of marketing in these countries.

Adult stem cells offer the same pluripotency of embryonic stem cells, but without the danger of forming teratomas (tumors), which remains a serious risk from embryonic stem cells. It is neither necessary nor desirable to use embryonic stem cells in the treatment of Crohn's disease or other disorders, since a growing number of studies are showing increasing success with adult stem cells. In fact, the only stem cell studies that have ever shown success in the treatment of any human disease have involved adult stem cells, since no study has ever been conducted in which a disease was successfully treated with human embryonic stem cells, although this fact is not generally reported by the media. Ever since researchers first isolated human embryonic stem cells in 1998, there has never been a successful treatment for any human disease in a human being by embryonic stem cells. Embryonic stem cells have in fact proven to be very problematic, whereas bone marrow stem cells, by contrast, have been safely used by doctors for over 40 years. Human umbilical cord blood in particular is now known to be a rich source of growth factors and cytokines, both of which are necessary for the regeneration of tissue, and stem cells that are derived from human umbilical cord blood have been shown to be more effective at tissue regeneration than are other types of stem cells that lack such additional factors. Ethics and politics aside, adult stem cells are highly preferable to embryonic stem cells purely for scientific reasons. (Please see the section entitled "Stem Cell Primer" for an explanation of the differenet properties of the different types of stem cells).

Adult stem cell therapy offers a potentially effective treatment of a chronic disease which previously has been considered incurable.


 

Copyright © 2004, 2005, 2006, 2007, 2008 Cell Medicine   Disclaimer   Terms and Conditions   8/18/2019