Singapore, Dec 5, 2009: Stem cells have long been proposed to hold promise for the treatment of a wide variety of diseases. Interestingly, last year saw some major breakthroughs in the development of stem cells as therapeutic products. Generally, it is accepted that there are three types of mammalian stem cells. Embryonic stem cells derived from the inner cell mass of blastocysts have the ability to differentiate into all of the specialized embryonic tissues. In contrast, adult stem cells derive both from adult tissues where they act as a repair system for the body by replenishing specialized cells and maintaining normal turnover of organs with high regenerative capacities, such as blood, skin or intestinal tissues as well as from sources such as umbilical cord, blood and bone marrow, which give rise to highly plastic adult stem cells. Most recently, there has been much interest in mesenchymal stem cells (MSCs) which are adherent cells isolated from the bone marrow or adipose tissue. Unlike other stem cells, these cells seem to be able to evade the host immune system, due to the lack of MHC protein expression. All three cell types have advantages and disadvantages as therapeutics.
Approved stem cell clinical trials
The year 2009 started off as a milestone year for stem cell therapists with three of the leading biotech companies (ReNeuron of Guildford, UK; Geron of Menlo Park, California; and StemCells of Palo Alto, California) received approval by the relevant regulatory authorities to proceed with clinical trials involving the transplantation of either foetal stem cells into the brain or of embryonic stem cells into the spinal cord. All these biotech companies are working with well characterized cells that have been extensively tested in animal models, and where preclinical data on safety and efficacy is available. This is also a good news for Asian biotech in general and Singapore in particular, since there are a number of companies at the forefront of stem cell research in this region
Encouragingly, data is already available from StemCells’ groundbreaking clinical trial to test the safety and preliminary efficacy of their proprietary HuCNS-SC product. The cells were tested in children with a rare neurodegenerative disease and shown to yield both a favorable safety profile of the product as well as evidence of engraftment and long-term survival of the donor cells.
In July 2009, a UK listed biotech company, ReNeuron announced that the UK Gene Therapy Advisory Committee (GTAC) had issued a Favourable Opinion subject to conditions in respect of ReNeuron’s proposed phase I clinical trial with its ReN001 stem cell therapy for stroke. This development follows on from the earlier Provisional Opinion given by GTAC in May. Importantly, the conditions attached to the Favourable Opinion relate to clinical trial protocol amendments and the provision of supplemental, non-safety-related, pre-clinical data. Regulatory approval for the clinical trial was granted by the UK Medicines and Healthcare Products Regulatory Agency (MHRA) in January this year, as ratified by the Commission on Human Medicines and its Clinical Trials Expert Advisory Group. The phase I trial will take place in Scotland at Glasgow’s Southern General Hospital, in patients who have been left disabled by their stroke.
In contrast, the US Food and Drug Administration (FDA) has placed Geron’s human embryonic stem cell therapy trial for spinal cord injury on hold, because it is reviewing non-clinical animal data submitted after the investigational new drug (IND) filing. The IND covers the study of GRNOPC1 (hESC-derived oligodendrocyte progenitor cells) that have demonstrated remyelinating and nerve growth stimulating properties. The new data submitted to the FDA was derived from studies to enable dose escalation and application of the product to other neurodegenerative diseases. Geron has also been performing additional product characterization studies and conducting further animal studies.
Establishment ofcommon regulatory guidelines
Stem cell therapies, like any other newly developed therapy, are subject to existing clinical trial regulations related to informed consent, clinical follow-up, independent expert review and institutional support and accountability. However, an important development that occurred last year with respect to stem cell therapies has been the establishment of additional strict guidelines. These guidelines were originally proposed and unveiled at the annual meeting of the International Society for Stem Cell Research (ISSCR). The guidelines for stem cell therapy are important for the future of stem cell therapies, since they aim to ensure that (i) best practices are applied to the clinical translation of stem cell research from the laboratory to human subjects, (ii) desperately ill patients are able to more objectively assess the value of curative experimental stem cell therapies and, (iii) such patients will not have to travel thousands of miles unnecessarily, and waste valuable time in search of stem cell therapies that are not based on sound pre-clinical data
All types of human stem cells and their direct derivatives are addressed by the guidelines, which focuses on three major areas of the clinical translational process (i) cell processing and manufacturing, (ii) pre-clinical studies and, (iii) clinical research. The guidelines also make specific recommendations for ethical oversight, peer review of studies, informed consent and protection of subjects, avoidance of conflict of interest, clinical trial design and reporting as well as long-term follow up of patients.
First documented stem cell related solid tumor
Until recently, the only type of tumor associated with stem cell transplantation had been donor-type leukaemia that occurred after haematopoietic stem cell transplantation, and is most often associated with transplantation of cord-blood derived stem cells, rather than adult bone marrow or peripheral blood derived stem cells, since these cells are more immature and potentially more prone to transformation. It has long been realised that human embryonic stem cells can give rise to teratomas in animal models, a fact that has raised safety concerns about the use of such cells in human patients. But until recently, there was no evidence that tumors can arise in humans treated with stem cells. However, in February 2009, it was reported that transplantation of neural stem cells from multiple donors led to brain tumor in a boy with ataxia telangiectasia--. Around four years post-transplantation, the patient was diagnosed with a multifocal brain tumor. Analysis of the tumor after surgical excision of the malignancy revealed a low-grade glianeuronal neoplasm that was derived from the cells of at least two of the donors. It has been reported that after the surgery, the child is in a stable condition.
The report was greeted by a flurry of editorials and commentaries as well as press releases by biotech companies involved in the Publicationdevelopment of stem cell therapies. The newly introduced ISSCR guidelines were not available when this treatment was undertaken. Indeed, stem cell therapies that are now being developed as therapeutic agents, use only well defined cells.
Can stem cells therapies be made safer?
It has long been known that the number of cells administered to an animal or patient influences the tumorigenic potential of the cells. For example; in immunocompromised animal models—even relatively non-tumorigenic cells can result in tumors if high enough doses of cells are administered. There are possible strategies to increase or enhance the safety of stem and other cell therapies. One such strategy involves the genetic modification of cells to express suicide genes. These gene encode enzymes which activate nontoxic prodrugs—upon administration of the prodrug, the activated metabolite preferentially kills dividing or replicating cells. Suicide genes are thus a fail-safe device so that if the stem cells show any inappropriate activity then they can be induced to die by administration of the prodrug. Such prodrug activating enzymes are being employed as part of gene therapy regimes to treat cancer by companies such as Ark Therapeutics, who are seeking market authorisation for such a treatment for brain tumors. A potential downside to this kind of approach as a safety device is that many of these suicide genes encode enzymes of bacterial, virus or yeast origin; so the cells may be recognised as being foreign, and thus be eliminated by the immune system before they can have their therapeutic effects.
The use of encapsulation technologies or delivery devices may provide additional safety for stem cell therapies. Living cells can be encapsulated in cellulose sulphate, alginate, or phycomer beads. Such encapsulated cells survive for long periods inside an immunoprotective scaffold or shell which is porous. Implantation of such encapsulated cells allows the production and release of therapeutic factors and even either physiological or engineered control of this process. Microbeads made of polymers of cellulose sulphate are particularly of interest since they have already been tested in patients for up to two years without any evidence of adverse events. GMP production is possible, encapsulated cells can be frozen for long term storage and many cell types have been successfully encapsulated.
Encapsulation of cells would allow suicide genes to be used as a fail-safe, since regardless of the material used, encapsulated cells are protected from the host immune system. Encapsulation of cells is not an option if the stem cells have to physically integrate into the patient’s tissue to provide a therapeutic effect. However, evidence has been accumulating that contrary to popular belief, stem cells do not replace dead, dying or functionally inactive cells since their therapeutic effects can be measured quite rapidly after implantation. It seems more likely that stem cells exert their therapeutic benefits via paracrine effects by immunomodulation, producing survival factors, wound healing mediators, anti-inflammatory and apoptotic factors as well as recruiting the body’s own stem cells. All in all, yet further good news is on the horizon.
Dr Brian Salmons is the co-founder of SG Austria (Austrianova Singapore), a Singapore-based biotechnology company that specializes in the encapsulation of living cells. He was the scientific director of Bavarian Nordic from its establishment in 1994 to 2001. Dr Salmons co-invented a cell encapsulation technology shown to be safe and efficacious in a phase I/II clinical trial. He co-founded the biotech company, Austrianova, a spin out of the Veterinary Medicine University in Vienna.
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