Stem Cell Therapy:

Helping the Body Heal Itself.

Stem cells are nature’s own transformers. When the body is injured, stem cells travel the scene of the accident. Some come from the bone marrow, a modest number of others, from the heart itself.There, they may help heal damaged tissue.

What are stem cells ?
“Stem cells” are defined as such cells which are able to continually renew themselves, thus to produce daughter cells and, additionally, to differentiate into different cell types. Depending on the particular class of stem cells they have the potential to reproduce all cells of the body or only defined cell types. The former ability particularly applies to embryonic stem cells and the latter ability applies to adult stem cells. The ontogenetic age of stem cells hence comes along with their differentiation potential: the ontogenetically youngest stem cells are embryonic stem cells from which later the somatic stem and progenitor cells emerge.

Embryonic stem cells (ES cells) have the ability to differentiate into cells of all three germ layers (endoderm, ectoderm, mesoderm) and into germline cells both in vivo and in vitro. Accordingly, they are able to differentiate into any type of cells of the body, and therefore are termed pluripotent. ES cells are derived from the inner cell mass (ICM, also called embryoblast) of the blastocyst after an in vitro fertilization during the embryonic phase. By this means, they can be established as cell lines in vitro.

Since the preparation of ES cells comes along with the damage of embryos research on human embryonic stem cells (mostly abbreviated as hES cells) caused an intense ethical debate within the society which is even continuing today. Therefore, the legislative body strictly regulates corresponding research in the German Stem Cell Act (Deutsches Stammzellgesetz, StZG) and allows research only under strict conditions (Key date regulation). In Germany the preparation of hES cells is illegal according the Embryo Protection Act (Embryonenschutzgesetz (EschG)).

Adult stem cells :
In contrast to the embryonic stem cells deriving from an early stage embryo there are still stem cells in large number of tissues in adult bodies which have, however, very limited differentiation potential (“multipotent”). These cells are able to give rise to specialized cells over the entire life time of the organism.

These adult, multipotent stem cells are particularly found in tissues such as bone marrow, skin, adipose tissue as well as in the brain, liver, salivary gland, root of a hair and elsewhere. In comparison to embryonic stem cells they typically have a reduced self-renewal capacity and clearly limited differentiation potential. The differentiation of certain adult stem cell types into lineages of all three germ layers (“transdifferentiation”) has been described in various studies but remains controversial.
Adult stem cells are found in each individual such they are applied as autologous cells for the development of therapeutic approaches. As autologous cells their rejection by the immune system is much more unlikely as compared to ES cells. In addition, it is being assumed that tumour genetic alteration of adult stem cells is rather improbable. Until now, tumor genetic alterations as a consequence of the clinical application of adult stem cells has not been observed.

Stem Cell Therapies- State of the art and future perspectives
Self-renewal – also called regeneration – is a process which the body is able to maintain up to a determined level. According to the latest research results, organs such as bone marrow, liver, and intestine have a high regeneration potential by a continuing cell renewal. This process is based on the resident stem cells of these organs. Other organs such as the heart and the brain are less regeneration-capable.By means of stem cell therapies damaged cells are to be replaced by applied stem cells. This means, that stem cells differentiate in vivo to target cells or they stimulate the neighbouring tissue to generate functioning cells (paracrirne effects). Because of the predominant legal situation in terms of the application of embryonic stem cells in Germany, so far, the research focuses on the adult stem cell therapy in the clinical field. The breakthrough for the first stem cell therapy was already in 1969 – i.e., the bone marrow transplantation for the treatment of leukemia.

To close chronic wounds, for example, outer root sheath stem cells have been used to generate skin cells. The resulting skin flaps are then put on the wound of the patient for engraftment. In the field of cardiovascular diseases where mostly autologous bone marrow-derived stem cells are applied notable promising results have been gained. In this area the approaches are under way to standardized therapeutic application.
A general reimbursement for these therapies by the compulsory healthy insurance does not exist yet but reimbursement in individual cases is possible. To date, only few products received the approval as an “Advanced Therapy Medicinal Product” in Europe and in Germany, respectively. Among them are some products for the treatment of damaged articular cartilage and a method for urethral reconstruction with oral mucosa cells.

What is cardiac stem cell therapy?
In Germany, every year about 280.000 people suffer from heart infarction caused by blockage of one or several coronary blood vessels. The neighbouring myocardial tissue then can not sufficiently be supplied with oxygen and nutrients and may finally die. The heart is hardly able to regenerate or to repair the damaged tissue by itself.
The currently applied common treatment of myocardial infarction by by-pass surgery or stent implantation improves the quality of life and the life time of the patients. However, the original effectiveness of the heart can not be restored. Therefore most of the patients suffer from chronic sequelae. In case of a severely damaged myocardium an organ transplantation can not be avoid. Researchers have recently succeeded to discover cardiac stem cells within the myocardium, however their cell number is very low such that they are not able to regenerate the damaged myocardium after severe diseases such as after a myocardial infarction. The “regrowing heart” is currently still a vision. Various research approaches are being pursued to reach this goal. For instance, it has been shown that mouse and human embryonic stem cells were able to differentiate to myocardiocytes after treatment with growth factors. Hence, this implies that one day these cells could potentially replace the dead myocardiocytes.
One innovative treatment approach which has successfully passed a clinical study and is already being used for therapeutic application is the stem cell therapy with autologous bone marrow-derived stem cells. These cells have intramyocardially been applied to the damaged area of the heart to replace and regenerate the damaged target tissue.
At the Clinic and Policlinic for Cardiac Surgery of Rostock a therapy has been developed to treat patients with autologous stem cells additionally to a by-pass surgery after a myocardial infarction. For this purpose, defined stem cells are isolated from the bone marrow of the patient and are intramyocardially injected into the damaged area of the myocardium during the by-pass surgery. The stem cell population used for the “Rostock Therapy” is identified by the marker CD133 on the surface of the cells.

How do we generate stem cells for the therapy?
At the RTC all applied stem cell preparations have been manufactured according to the actual pharmaceutical law. This makes sure that the requirements of the “Pharmaceuticals and Active Agent Manufacturing Ordinance” (German: “Arzneimittel- und Wirkstoffherstellungsverordnung” (AMWHV)) for the application of “Good Manufacturing Practice” (GMP) and for the manufacture of products of human origin according to the “Codes of Good Practice” (Gute Fachliche Praxis, GFP) are met. Currently, all of our stem cell products are being produced by a manufacturer with the corresponding authorization.Reduced production times by widely automated processes stimulated us to focus on „Point of Care“(PoC)-manufacturing (on-site patient care) of stem cell products. By means of such GMP-compatible procedures we will manufacture such medicinal products on our own by “Point of Care” practice in those cases which are advantageous. For this purpose we have installed production sites close to the operation halls in agreement with GMP requirements and we have established appropriate measures for quality assurance. In the near future we will apply to receive authorisation for manufacture from the local authorities.

How is the status of clinical development at the RTC?
PERFECT – first Phase III stem cell trail for heart regeneration

Autologous stem cell products for the cardiac application have been classified as “Advanced Therapy Medicinal Products” and are underlying the strict regulations of the Medicines Act. For this reason, quality, efficacy and safety for the application in human beings have to be proven before putting such a product on the market. During the period between 2001 –2005 clinical Phase I/II trials have already been performed in Rostock for the proof of safety and efficacy of the intramyocardial therapy with bone marrow-derived CD133 stem cells after myocardial infarction parallel to a bypass surgery.

With these trials we were able to demonstrate the safety of the therapy and a first indication of a significant improvement of the heart pump function. After that, in 2009, the first randomised double-blinded multicentric clinical Phase III trial PERFECT has been initiated in Rostock. With this trial proof of safety and efficacy should systematically be provided. The trial in which six well-known heart centres in Germany are involved is performed according to the internationally approved requirements of “Good Clinical Practice” (GCP).