Background Information

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1 Background Information 1. What are stem cells? 2. What might stem cell research achieve? 3. Why we need to continue research using embryonic stem cells? 4. Time taken for discoveries 5. Examples of stem cell therapies in clinical trials 6. Patentability of human embryonic stem cell therapies 7. Creation of Embryonic cell lines 8. Fertility Research using human embryos and blastocysts 1. What are stem cells? Stem cells are master cells, which can divide and renew themselves almost indefinitely, but can also mature into specialised cells such as muscle and nerves. There are four main kinds of stem cell: Human Embryonic stem cells (hes): these cells, taken from blastocysts 1, can become almost any type of specialised cell they are pluripotent 2. The most common source is from very earlystage embryos (less than 7 days old) donated by couples undergoing IVF. Induced Pluripotent Stem cells (ips): These are obtained by reprogramming adult cells to regain the properties of pluripotent cells. The methods and ability to characterise the cells depends on knowledge obtained from studies of ES cells. While of clear importance for studying aspects of genetic disease, there is still uncertainty as to how safe they would be for therapies based on transplantation, as the extent of reprogramming is variable and the original adult cell from which an ips cell line has been derived may have been abnormal. Adult stem cells: these cells, found in many organs and tissues, ensure tissue turnover and repair e.g. in bone marrow, skin and intestinal epithelium, can only develop into a limited number of specialised cell types. Foetal stem cells: these are obtained from either aborted foetuses or biopsies under strict regulation. They have been established from several types of tissue, such as the central nervous system, neural crest, the amnion or umbilical cord blood. These stem cells tend to have broader potential than adult stem cells, but the range of cell types to which they give rise are similarly restricted, depending on the stage and tissue of origin. 2. What might stem cell research achieve? Degenerative diseases threaten the dignity and integrity of patients and without regenerative therapies these diseases are untreatable. Regenerative medicine provides a promising avenue to TREAT or CURE: Neurodegenerative diseases, such as Parkinson s and motor neuron diseases, that are set to increase with an ageing global population. 1 Blastocyst: a developing ball of cells which can give rise to an embryo if implanted in a human. 2 Pluripotent: the ability of a stem cell to form any type of specialised cell, such as muscle or nerve.

2 Ophthalmologic conditions, where stem-cell derived tissue might be used to treat age related macular degeneration, a major cause of blindness in the elderly, as well as congenital eye conditions and corneal damage.e Chronic conditions such as diabetes e.g. by introducing functional beta-islet cells to make insulin in patients, or to create artificial skin to manage diabetic ulcers. Traumatic injury such as spinal cord damage and stroke, e.g. by introducing cells that can either stimulate endogenous nerve cells to regenerate, or to replace lost nerve cells. Cardiovascular conditions such as heart failure (e.g. by introducing stem-cell derived heart cells that regenerate heart muscle and help repair damage) In the long-term it is hoped that methods will be developed to harness the existing stem cells within patient s bodies to repair in response to disease or injury. It is envisaged that this could use small molecules and would avoid the need to maintain stem cells outside of the body, to transplant back into patients. Although not regenerative themselves there are several associated technologies using stem cells with great therapeutic potential. Stem cell therapies are being developed to be used as drug delivery systems e.g. stem cells could bring chemotherapeutic agents directly to targeted cancerous cells. ips cells can be used to make models of human disease to investigate their causes at a cellular level. Well-characterised models can provide platforms for screening new drug candidates in human cells, accelerating pharmaceutical drug development, and they can provide better models for toxicology testing than the traditional animal ones used, decreasing the number of new drugs that fail in phase II/III clinical trials due to unexpected differences between animals and humans 3. Why we need to continue research using embryonic stem cells Although much progress has recently been made in the development of induced pluripotent stem cells, coupled to the promise of new approaches using direct trans-differentiation, side-by-side research with all types of stem cells is still required for the foreseeable future as it is still unclear which route will be the most effective. The reasons for this are: Safety and function: hes cells are normal human embryo cells, whereas ips and trans-differentiated cells are created by reprogramming adult cells using molecular engineering. There are subtle but important differences in the behaviours of these different cell types, most likely reflecting epigenetic differences that are not fully understood, while more critically the engineering technologies currently being utilised to create ips cells do not leave them safe enough to transplant into people. hes cells remain as the gold standard stem cells and are therefore required to test the safety and differentiation of ips cell therapies as they are being developed. Ready for the clinic: A number of adult stem cell-based regenerative therapies are undergoing clinical testing, utilising minimally manipulated cell populations, for the most part derived from

3 donor bone marrow stem cells. These offer promise in a limited number of disease-areas, given the restricted ability of such cells to differentiate into other tissue-types, and build on the longestablished success of bone-marrow transplantation in cancer treatment. Over the past couple of years, a number of clinical-grade human embryonic (hes) cell lines have been generated to support early phase human trials and in the past 12 months hes cell derived therapies have been successfully achieved regulatory approval for use in clinical trials to treat both macular degeneration (blindness) in the EU and US, and spinal cord injury (in the US). The use of ips cells offers a much greater range of possibilities for regenerative medicine, as well as the potential for unlimited supplies of donor cells. To be of a standard to be transplanted into people, such cell lines or their derivatives must be of a very high quality, purity and stability, otherwise there is a risk of inappropriate behaviour in the recipient of such transplants, with cells either creating the wrong type of tissue or leading to the formation of tumours. The nature of the technology currently being used to generate ips cell lines means that issues remain before they can be developed to this standard, whereas some embryonic cell lines have already been developed to this standard. Discovery and innovation: It is noteworthy that the basis of ips cell technology is entirely based on our understanding of embryonic stem cell biology, and that the potential for new innovations in the field will best be maintained through encouraging parallel approaches in stem cell discovery science. 4. Time taken for discoveries Critics argue that stem cell research has not delivered therapies over an extended period of funding for the research. However stem cell research and specifically human embryonic stem cell research is a relatively new field. James Thompson discovered how to isolate and human embryonic stem cells in Comparatively, other therapies currently in use, for example monoclonal antibodies, have taken up to 25 years to develop into large-scale therapeutics. The first reliable sources of monoclonal antibodies were first developed in The first therapeutic monoclonal antibody was not approved for therapeutic use until The explosion in the use of monoclonal antibodies for therapeutic use did not occur until 2000 onwards. These therapies are now widely used to treat cancer, and other autoimmune and inflammatory disorders. Indeed the average time for development of a therapeutic drug from the pre-clinical research stage is approximately 15 years. 3 Similarly, most existing therapies based on stem cells make use of some of the first stem cell types to be identified, about 50 years ago, notably those of the blood system, haematopoietic stem cells (HSCs), but which are restricted to diseases relevant to the tissue of origin. It is therefore imperative that all avenues of stem cell research are kept open and proportionately regulated until scientists are able to find the optimal techniques and materials to develop therapies. It is hoped that technologies and advances in ips cells may one day render it unnecessary to use hes cells however until that point, limiting the use of hes cells risks cutting off avenues to develop therapeutics and new knowledge which will benefit biomedical developments. Fields particularly reliant on stem cell research include: 3

4 Regenerative Medicine: The ability to investigate all types of stem cells (including human embryonic stem cells) with potential to make advances in regenerative medicine is vital to developing treatments for patients and maintaining Europe s global ranking in this competitive research field. Stem cell research has the potential to lead to the development of treatments and therapies for patients suffering from diseases and illnesses including incurable neurodegenerative conditions such as Parkinson s, motor neurone diseases, multiple sclerosis, as well as chronic conditions such as type 1 diabetes, cardiovascular conditions, liver damage, spinal cord damage, stroke and blindness. Many of these conditions will increase in prevalence with an ageing population. Clinical trials using human embryonic stem cell derived retinal cells are currently being progressed in Europe for the treatment of Stargardt macular dystrophy, a form of blindness in juveniles, and age-related macular degeneration, the most common form of blindness that affects 1 in 4 people over 60. This field of research remains complex. To enable scientists to best understand the massive potential of stem cells, scientists must be able to continue research in all avenues of stem cell research: this includes using adult, induced pluripotent, embryonic and fetal stem cells. Induced pluripotent stem (ips)cells, based upon knowledge gained using embryonic stem cells, hold great potential in regenerative medicine, but as yet cannot replace embryonic stem cells and further characterisation is needed before we can be sure they are safe for clinical use. It is too early to tell which stem cell type will be the most effective, for ultimate clinical use, so it is essential to keep all avenues of research open. Any move to now make human embryonic stem cell research ineligible for Horizon 2020 funding would risk holding back progress across the entire field and make Europe a less competitive place to undertake research. Reproductive health research: Banning all funding for research related to the destruction of embryos will significantly impede research in various aspects of reproductive health, such as fertility, recurrent miscarriage and severe developmental disorders. This includes research in a number of techniques used during In- Vitro Fertilisation (IVF) treatment such as improving methods of embryo freezing, culture and embryo selection to increase the chances of a successful outcome to the IVF procedure and fundamental research to understand fertilisation. Europe leads the world in Assisted Reproductive Technology, initiating approximately 55% of all reported ART cycles. 4 Genetic disease research: Banning all funding for research related to the destruction of embryos will significantly impede research on various aspects of genetic disease, such as on chromosomal abnormalities and pre-implantation Genetic Diagnosis (PGD). 5. Examples of stem cell therapies in clinical trials There are a number of stem cell therapies currently in clinical trials. Clinical trials are currently underway to see if stem cells can repair damaged tissue in several conditions: In Europe and the US, there are trials investigating the safety and efficacy of injecting stem cells into heart muscle as a treatment after heart failure. 4

5 In Switzerland, Stem Cells Inc. are implanting cells into patients with spinal cord injuries to assess safety but the long term aim is to regenerate and recover function. 5 In the UK, ReNeuron are undertaking a clinical trial testing the safety of foetal neural stem cells as a treatment for patients with stroke. 6 In the UK, patients at the UCL Institute of Ophthalmology in London are participating in an international clinical trial sponsored by the US company Advanced Cell Technology (ACT) to test an hes-based treatment for the incurable condition Stargardt Macular Dystrophy (a form of blindness prevalent in juveniles), which represents Europe s first clinical trial using embryonic stem cells In the US, a clinical trial is being conducted to evaluate the transplantation of hesc-derived retinal pigment epithelial cells into two patients with dry macular degeneration, the leading cause of blindness in the developed world. 7 Primary results of the trial identified visual improvements in the patients and an absence of tumour formation. A related trial is soon to commence in the UK, using hesc-derived retinal pigment epithelial cells to treat age-related macular degeneration. The study, to be led by Professor Peter Coffey at the UCL Institute of Ophthalmology in London in partnership with Pfizer 8, is currently awaiting final regulatory approval. A phase-1 clinical trial using hesc-derived heart cells for the treatment of heart failure is anticipated within the next 4 years in humans, following a recent breakthrough in monkeys, where the transplantation of these cells successfully regenerated and remuscularised heart tissue, repairing up to 40% of damage 9.In the longer term there are possibilities for stem cell therapies for diabetes (beta-islet cell replacement), Parkinson s disease and a stem cell-based therapy for a common form of hearing loss in humans (auditory neuropathy) based on research in gerbils. 6. Patentability of human embryonic stem cell therapies The European Court of Justice decision in Brüstle v Greenpeace has called into question the patentability of therapies derived from human embryonic stem cell lines. Various legal minds believe that the Brüstle decision and the inability to patent human embryonic stem cell products should not preclude the ability to commercialise and exploit such products for the following reasons: (a) it will be possible to obtain such patents in other jurisdictions (including the US); (b) other aspects of any therapy (such as biomarkers, diagnostics, specific treatments or complex technologies used to turn hescs into treatments) may still be patentable in Europe; (c) inventors (and their advisers) will use alternative ways to protect their intellectual property (e.g. through licensing know how) o notwithstanding the decision; NCT : and NCT :

6 Many scientific and medical advances are in fact made on tissues or cell lines that are not patentable or patented, for example monoclonal antibodies were originally not patented by the UK Medical Research Council, and yet now make up around a third of all new drug treatments for various major diseases. Indeed an absence of patent protection could potentially create a European research haven and attract hesc researchers. Furthermore we must remind ourselves that publicly funded research is conducted for patients, not patents. The CJEU s decision in Brüstle will not impede hesc research, however if EU funding were to be cut stem cell research and expertise could dramatically slow down Europe and be lost to other territories, such as the US, where there is no such ban. 7. Creation of Embryonic cell lines Technology has developed to the extent that the destruction of an embryo is not required to undertake research. Embryonic stem cell lines which are initially developed from a blastocyst are kept in stem cell banks all over the world, scientists are able to use these to grow more embryonic stem cells in the laboratory. Where new cell lines are made, the blastocysts used are in the vast majority of cases those remaining after IVF treatments especially where cryostored after families have been established, and by willing consent of the patients, These blastocysts would otherwise be discarded. It would seem far better to use these for research where potential treatments for disease for future generations can be developed rather than discarded as biological waste. It would seem far better to use these for research where potential treatments for disease for future generations can be developed rather than discarded as biological waste. 8. Fertility Research using human embryos and blastocysts The treatment of infertility and the laboratory techniques that underpin it are relatively new. The field of Reproductive Science is highly dynamic as researchers and clinicians strive to improve the safety and efficacy of the treatments available to patients. Without the freedom to perform ethically approved and patient consented research and development work on patient gametes and embryos, which are not suitable or required for their own use, clinical breakthroughs such as Intracytoplasmic sperm injection (ICSI), which revolutionised the treatment of male factor infertility and Pre-Implantation Genetic Diagnosis (PGD), which allows embryos at risk to be tested for serious genetic disease before they are transferred, would not have been possible. There are still many challenges facing scientists working to ensure that safe and effective fertility services are available to as many people as possible. Research such as that taking place to develop a clinical treatment to enable people with life-threatening or debilitating mitochondrial diseases such as muscular dystrophy to safely develop embryos which will be free of the condition is one very good example of how critical human embryo research and development is to the future of Reproductive Science and the people who will depend on these techniques to start a family.