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The use of stem cells in clinical trials

Stem cell therapy is currently generating much excitement both in the public and scientific arena for its potential to treat a range of clinical conditions. However, it is worth reminding ourselves that stem cells have actually been in use in the clinic for over 40 years, namely in the form of bone marrow transplants. Indeed the first successful bone marrow transplant in humans was in 1968. It should be noted that the bone marrow and blood derived donor cells used for transplanting do not represent pure populations of stem cells, rather they contain trace amounts of the “active ingredients”, in this case haematopoietic stem cells (HSC). In both HSC and other stem cell fields, the use of highly enriched stem cell populations is still uncommon as clinical results can still be obtained.

The HSC field has a relatively long and well known clinical history, however, the mesenchymal stem cell (MSC) field has expanded greatly in the past few years and is now rapidly going through the clinical trial process for the treatment of a number of conditions.  MSC give rise to mature cells that produce supportive (or connective) tissues in the body such as bone, cartilage and fibrous tissue that give organs their structure. Many potential clinical applications are already being tested with MSC. Unlike HSC, MSC have the advantage that they can be expanded (increased in cell number) in the laboratory, thus a relatively small donation may allow treatment of many individuals.

MSC are highly multipotent, this means that they have the ability to switch into several different cell types including bone, cartilage, muscle, marrow stroma, tendon and, fat. What is exciting about MSC is their apparent ability to assist in tissue repair even in organs other than from which the MSC were derived and to resist or even suppress immune responses.  Immune responses are the bane of the transplanter leading to rejection of the donor tissue by the immune system of the patient.

The extraordinary immune-suppressingnature of MSC has also lead to their potential use in an allogeneic (unrelated donor) setting without the use of immune-suppressants, or even in pathological autoimmune settings such as graft-versus-host-disease (GVHD).

Osiris Therapeutics (www.osiristx.com) in the US and Australia’s own Mesoblast (www.mesoblast.com) have shown that laboratory-expanded unrelated allogeneic and autologous (patient’s own cells/tissue) MSC provide significant benefits in several tissue reparative settings. Osiris Therapeutics has now conducted an FDA-approved Phase I clinical trial in the myocardial infarct (heart attack) setting, the results of which include a four-fold reduction in arrhythmias (mistimed heart beats), reduced premature ventricular contractions (the ventricles are the driving force of the heart’s pump action) and surprisingly an unexpected improvement in lung function. Despite this, there has been no evidence to date of MSC turning into heart muscle cells themselves, which is one of the goals that the stem cell field is trying to achieve. Mesoblast and its associated US company Angioblast Systems Inc. have started clinical trials in cardiac repair, bone repair and in the bone marrow transplant setting with both MSC and HSC co-transplanted together. These clinical trials indicate that MSC actually enhance HSC recovery in bone marrow transplants.

In phase II clinical trials, there is evidence that MSC are therapeutically beneficial in human studies of GVHD. Administration of MSC has been reported to be of therapeutic value in patients with Crohn’s disease where adipose-tissue-derived autologous MSC inoculated into fistulas caused by Crohn’s disease resulted in healing of six of nine fistulas.  

Stem Cells and the treatment of Genetic Diseases

Stem cells also hold promise for the treatment of inherited genetic disorders. One of the first conditions to be tested was that of severe combined immunodeficiencies in children. These children have a mutation that leads to such poor production of immune cells that death from infection is inevitable. There have now been clinical trials, where HSC were removed from the patients and the mutation corrected using viruses to transfer the correct genes into the DNA of the patient cells. When the HSC were transplanted back into the patient, an amazing recovery of the immune system was seen. This is one of the first examples of personalised stem cell therapies using the patient’s own (autologous) cells. However, the dangers of genetic manipulation using viruses became sadly evident when some of the patients later developed cancers due to the transplant. Other stem cell therapies have also been attempted to correct genetic disorders, this time using unrelated stem cells, but which still contained copies of the correct (not mutated) gene. A potential severe although rare genetic disease known as osteogenesis imperfecta causes sufferers to have skeletal deformities and fragile bones. The condition is caused by a mutation in a crucial protein component of bone, naturally secreted by MSC or their progeny (osteoblasts). Although the low numbers of patients treated in this way precludes statistical analysis, low numbers of donor MSC did engraft and likely contributed to bone formation and reduced number of fractures relative to age matched controls. It is likely that in the future a range of other genetic conditions will be treated with stem cells. 

Therapeutic use of embryonic stem cells

To date only one clinical trial using human embryonic stem cells has received FDA approval for a phase I study. The study is being run by Geron, based in the US. The study group are people with thoracic spinal cord injuries with complete loss of locomoter and sensory activity below the site of injury. Interestingly the trial is limited to patients with recent injuries (within 14 days), as animal models have shown that stem cell treatment is ineffective at later time points, most likely due to scar tissue formation. The trial has been recently halted as the FDA scrutinise new pre-clinical data. Although Geron are using human embryonic stem cells, the actual treatment is with in vitro differentiated cells, that is, the stem cells that have already been switched into cells of the neural lineage by scientists in the laboratory. This trial has been recently halted as the FDA scrutinise new pre-clinical data.  

Stem cell tourism

Many countries with lower regulatory or ethical approval standards already have clinics advertising stem cell therapies for a range of conditions. Many (if not all) of these are offering unproven therapies (there may not even be any prior animal studies testing safety or efficacy). It seems that the promise of improvement, even if small, is enough to tempt those in desperate need.  The dangers associated with these types of unproven treatments are very real and have already been shown in at least one well publicised case. A young boy received an experimental stem cell transplant in Russia to treat a rare inherited disease (Ataxia Telangiectasia). He was later found to have developed tumours in his brain and spinal cord which had originated from the transplanted donor cells.

The future

Stem cells really do hold exciting potential for the treatment of a very large range of conditions. Ultimately the de novo generation of whole organs is foreseeable, although that goal remains well into the future. Indeed, many hurdles will still have to be overcome, namely obtaining good engraftment with function and, if using allogeneic material, avoiding immune rejection problems. Cells such as MSC may provide an “off the shelf” allogeneic stem cell treatment, but only clinical trials will prove if this is effective. In an ideal world, autologous stem cells would be used which avoid the problems of rejection, however, this would involve personalised medicine at a level never seen before, which faces enormous financial challenges due to the high expense associated with this type of treatment.  This has become even more of an issue with the advent of “induced pluritpotent stem cells” (iPS). These are adult cells from any tissue (eg a skin biopsy) that have been induced to revert back to stem cells with embryonic stem cell-like properties – that is they have the potential (with the appropriate encouragement) to become any cell type in the body. This opens the window on a completely new world of personalised medicine where the patient’s own cells are used to treat their condition without the ethical problems associated with embryonic stem cells. However, many challenges also lie ahead in terms of controlling the behaviour of these cells. As has already been shown, stem cell treatment can lead to catastrophic side-effects including the formation of cancers. The level of complexity involved in the development of the human body is quite staggering, and to assume that initial insights into stem cell behaviour will rapidly lead to tissue regeneration strategies in the clinic are somewhat naïve. I think that despite the promise of these cells and clinical successes to date (e.g. bone marrow transplants), we are still some way off from being able to repair or recreate complex tissues such as brain, spinal cord or heart.

For those wanting to know more about stem cell trials, a United States government run web site, www.clinicaltrials.gov provides regularly updated information about U.S. federally and privately supported clinical research in human volunteers. Sadly, no such site exists in Australia yet, where government funding of biomedical science as a proportion of GDP continues to lag well behind that of other developed economies. Currently, Australia has one public stem cell initiative, the Australian Stem Cell Centre, involving a partnership of the Federal and Victorian state governments, the goal of which is to support stem cell research with commercial potential. The Centre is funded until June 2011. The Centre provides stem cell information, which can be downloaded from their website.

Information about clinical trials in Australia and New Zealand can be searched
using the Australian and New Zealand Clinical Trials registry. An international website with clinical trial information is Clinical Trials Portal.

The International Society for Stem Cell Research has published guidelines for patients and families interested in stem cell research and treatments. This can be downloaded here. 

If members of the public are concerned or have questions about any of the issues raised here, they can contact the Australasian Society for Stem Cell Research at info(at)asscr.org.  

Useful websites:

Australian Stem Cell Centre

US government clinical trial database 

International Society for Stem Cell Research

Osiris therapeutics

Mesoblast 

Written by Gary Brooke, PhD
Mater Medical Research Institute
Raymond Terrace
South Brisbane
Queensland 4101