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It makes for good print copy and a great news story sometimes tagged on the end of a nightly news programme - a new "cure" is found for a particular disease and the news then fans out spreading hope and raising expectations. Timing and space issues do not allow reporters to investigate nor emphasise effectively the true complexities of commercialising promising drug candidates and device technologies. Similarly we rarely hear about the failures of a particular type of therapy - the other side of the coin as it were. This scenario certainly applies to stem cell technology and its place in regenerative medicine. Basic and translational research on stem cell biology has progressed rapidly over the last few years and is a burgeoning field. So much so that a lot of hope is invested in the potential clinical utility of stem cells across a range of illnesses and conditions. Not only hope is being invested in this area however. The large pharma companies have begun to take note and investment is being seen in an attempt to harness the potential in regenerative medicine. For example, in November 2008, Pfizer decided to invest $100m in stem cell research, creating facilities in the US and UK, including hiring 70 scientists to staff the labs.
There is no doubting the fascinating potential for stem cell therapies. Within this article we take the opportunity to highlight the activities of some of the companies that are actively seeking to commercialization of stem cell therapies. This is the real thrust of the article. In order to try and provide a balanced view of the potential in the market we will briefly outline some of the challenges we understand there to be with respect to achieving commercialization. An article of this size cannot do true justice nor add sufficient detail to the debate surrounding the use of stem cells in the clinical setting, so we strive directly to inform the reader on commercial activity and, where possible, comment on where we envisage the greatest potential to lie. The lack of primary data dictates that we do not provide a forecast of the market size of either the therapeutic banking nor the cellular therapeutics segments of the stem cell technologies market. Suffice it to say that the fascination with the development of this market ensures that we intend to provide forecasts for these sectors and a more complete analysis in future articles which we will post on our website.
A quick primer
Characteristics of Embryonic Stem Cells
One of the characteristics of an embryonic stem cell is that it can translate or it can divide or be differentiated into all the various cell types in the human body.
The first few of the early embryonic cells are totipotent, meaning that they are each capable of giving rise to an entire organism, including all the cell types that make up the embryo and the body, and all the cell types that make up the extra-embryonic supporting tissues, such as the placenta.
About five to seven days after conception, a zygote will have divided into about one hundred to one hundred and fifty cells. These take the form of a hollow ball called a blastocyst, with a mass of undifferentiated cells inside it. These undifferentiated cells are used to generate embryonic stem cell lines.
These embryonic stem cells are no longer totipotent, but they are still pluripotent, that is, they are capable of differentiating into all the types of cells that comprise a human being. They cannot form extra-embryonic
tissues (such as the placenta), and thus cannot give rise to a foetus.
After the embryonic stem cells have differentiated into the many types of cells that make up a foetus, a child, or an adult, most lose their ability to differentiate further. However, a small number, the adult stem cells, retain some ability to differentiate. These multipotent cells replenish and repair many of the cells of the body.
Adult stem cells are difficult to isolate, multiply, and maintain in culture. However, embryonic stem cells are more easily isolated, multiplied, and maintained in culture.
At least six embryonic sources have been used to establish human pluripotent stem cell lines. Traditional human embryonic stem cell (hESC) line generation from a blastocyst-stage embryo
hESC lines from human primordial germ cells (destined to become either oocytes or sperm cells)
hESC lines from dead embryos
hESC lines from genetically abnormal embryos
hESC lines from single cell embryo biopsy
hESC lines created via parthenogenesis
All approaches involve isolation of viable cells during an early phase of development, followed by growth of these cells in appropriate culture medium. The pluripotency and rapid proliferation make human stem cells attractive sources for cell therapy. However, there is a large enough lobby of those opposed to the use of embryonic stem cells derived from human sources in basic research that the opposition on ethical grounds to use such cells in the clinic is seemingly insurmountable. These concerns have led stem cell researchers across the globe to implement basic research programmes aimed at generating stem cells from sources other than embryos. Developments have advanced considerably in and since the middle of this decade through what is known as nuclear reprogramming.
Nuclear Reprogramming - a major step forward
Timeline + condensed notes
Mid 1950s In the 1950s the British embryologist Dr John Gurdon started his pioneering work in cell biology. Gurdon's early work showed that in nuclear transplantation experiments in the frog Xenopus laevis differentiated cells could be reprogrammed in the egg cytoplasm (nuclear programming). The first step of nuclear reprogramming refers to the erasure of the donor cell's epigenetic pattern following nuclear transfer and the re-establishment of embryonic epigenetic characteristics and gene expression in a cloned embryo. The second step of nuclear reprogramming refers to re-differentiation of cloned embryos from a totipotent status to a differentiated status for tissue/organ formation during post-implantation development. Genetic information is not lost as the body's different cell types specialise into a range of cells; rather, it is retained in the nuclear reprogramming process.
1977 - Ian Wilmut's team at the Roslin Institute, Edinburgh clone Dolly the sheep. Dolly was the first viable offspring ever derived from adult mammalian cells. To achieve their aims, researchers demonstrated that the procedure used was deceptively simple - they removed an unfertilized oocyte (egg cell) from an adult ewe and replaced its nucleus with the nucleus of an adult sheep mammary gland cell. This egg was then implanted in another ewe, and Dolly was the result.
2006 - Inducing pluripotency - Pluripotency can be artificially restored to human somatic cells by viral transduction of genes coding for stem cell factors. This process only requires SOX2 and OCT3/4 integration but the frequency of reprogramming is significantly increased by co-infection with virus coding for KLF4 and c-MYC.
Shinya Yamanaka - Institute for Frontier Medical Sciences, Kyoto, Japan. His group demonstrated the nuclear reprogramming of fully differentiated mouse skin cells into stem cells that can specialize into many fetal and adult types of cells. Yamanaka's team created the first generation of induced pluripotent stem cells (known as iPS cells) by adding four genes normally expressed only in embryos-Oct4, Sox2, c-Myc, and Klf4-to adult skin cells. They also added a drug-resistance gene and put it under the control of a gene, Fbx15, that is typically expressed in embryonic stem cells. The efficiency of the system was low - only about 0.1% of the total cells - the drug-resistant cells- had many characteristics of true embryonic stem cells, but the reprogramming was incomplete. Notably, when iPS cells were added to mouse embryos, no live pups were born (embryonic stem cells added to early -stage embryos normally contribute to all tissues in live mice).
Also established iPS cells from adult human dermal fibroblasts by introducing same four factors.
iPS cells are similar to embryonic stem (ES) cells in morphology, proliferation and teratoma formation.
Reactivation of the c-Myc retrovirus in these experiments results in an increased tumorigenicity in the chimeras and progeny mice, thus raising considerable fears about the application of the technology for clinical purposes.
2008 Yamanka's group developed a modified protocol without using the Myc retrovirus. Elimination of c-Myc drastically reduced tumorigenesis, as measured by cancer-related deaths of chimeric mice derived from iPS cells. We also generated iPS cells from adult mouse liver and stomach cells.
2008 Furthermore, we were able to generate human iPS cells from adult dermal fibroblasts without MYC.
2008 Yamanaka group succeeds in generation of mouse iPS cells without transgene integration into genome by using plasmid DNA.
2008 Improving iPS Cells
Konrad Hochedlinger and his colleagues at Harvard significantly improved the process of generating iPS cells with one simple change: his group put the drug-resistance gene under the control of the genes Nanog and Oct4. In gene expression and gene modification studies, the resulting iPS cells showed complete reprogramming, and they were also able to contribute to live mouse births.
While iPS cells will currently be of assistance to disease modelling and drug screening, random integration of genes is still seen as capable of presenting an oncogenic risk and so this approach constitutes a significant obstacle to using iPS cells therapeutically. The principal problem is that while the proof of principle has been demonstrated the molecular mechanisms by which the programming of pluripotency occurs is little understood. Coupled to this, the low efficiency of the techniques in terms of the number of cells programmed means there is insufficient information, to date, on which genes and which proteins and the concentrations of them which are critical to ensure pluripotency. If cell-based therapy is to reach its full potential, understanding of the cellular capacity for reprogramming, and continued comparison between methods of induction, is critical. The importance of the latter should allow identification of the "factors" that induce programming.
Current research efforts are of course seeking not only these answers but are also looking at how to remove the need for gene/plasmid vectors. Strategies are evolving to generate genetically unmodified or reprogramming factor-free iPS cells.
There is a need to realise the potential to make reprogrammed cells a source of patient-specific cells for use in medicine that will enable the body to regenerate, repair, replace, and restore diseased or damaged cells, tissues, and organs.
iPS Research Dictates Shift in the Market Business Models
As advances have been seen in generating induced pluripotent cells there is a feeling that the field of regenerative medicine has a clear opportunity to move from embryonic stem cells to iPS cells, taking away the negative sentiment associated with the ethical fears and controversies and providing a positive push to research and market opportunity.
The potential afforded by advances in iPS technology is also important in supporting the assumption that Future cell-based therapies will surely benefit from isogenic transplantation (i.e. cells from one patient, reprogrammed and differentiated for transplantation to that patient). The focus should shift from allogeneic products and thus treatments to autologous treatments which will be safer and generally more acceptable to patients and society as a whole
Obama's stem cell stance - Yes We Can
On March 9 2009 President Barack Obama overturned the previous Bush administration's eight-year-old restrictions on federal funding of research involving human embryonic stem cells. In doing so, President Obama paved the way for the National Institutes of Health to introduce new guidelines in the funding of embryonic and non-embryonic stem cell research which allowed US research scientists to use or conduct research on any of the hundreds of stem cell lines which have been cultivated and studied by other groups worldwide. Prior to President Obama's initiative American researchers were restricted to obtaining federal funding relating to work planned on the utilisation of the 21 lines of embryonic stem cells derived before August 9, 2001. With the entry of the US into the "mainstream" of basic stem cell research it is anticipated that the potential for innovation and commercialisation of therapies will be advanced. Time will tell whether the abolition of the ban on US federally funded stem cell research can truly deliver hope rather than confirm hype associated with the view that such research will enhance applications within regenerative medicine.
Analysing comments released by stem cell-focused companies it appears that they are indicating that while funds available to biotechnology remain elusive there seems to be some relaxing of the purse strings due to the more favorable political support of the Obama Administration toward stem cell technology.
Again, scientists and policy makers are however under no illusions that much remains to be learned about the mechanisms by which stem cells repair and regenerate human tissue, the optimal cell types and modes of their delivery, and the safety issues that will accompany their use. As these issues become clearer so the regulatory paths will become smoother and thus commercialization of the much anticipated cellular therapies enter the clinic.
Over the last few years, international groups have begun demonstrating the therapeutic potential of stem cells in a number of areas. We will review some of these possible applications in this article.
CELL THERAPY IN OPHTHALMOLOGY
Stem Cells - Targeting Corneal Blindness
For 15 years Russell Turnbull has been partially blind in one eye after ammonia was deliberately squirted into his eye. As a result of this mindless attack Mr Turnbull from Consett, County Durham in the North East of England has endured continued psychological and physical torment and received constant palliative treatment for a condition called Limbal Stem Cell Deficiency (LSCD). However, a stem cell treatment developed by a team of scientists and clinicians at NESCI, the North East England Stem Cell Institute (a collaboration between Durham and Newcastle Universities, the Newcastle Hospitals NHS Foundation Trust and other academic and commercial partners), has provided a positive benefit for Mr Turnbull and seven other LSCD patients. The stem cell treatment involved taking a small amount of stem cells from Mr Turnbull's good eye, cultivating them in a laboratory and then implanting them into his damaged cornea. As a result of the treatment Russell Turnbull stated that the sight through his damaged eye was now almost as good as it was prior to the accident and that the treatment had transformed his life. Encouraged by these results there are plans for the NESCI treatment to be made available in other clinics and is one recent example of the potential that lies in stem cell therapies for ophthalmic disorders.
Disease or injury to the cornea can make it go cloudy, leading to impaired vision. The lack of a sufficient supply of donor corneas means that treatment options are limited and this fact drives research into furthering our understanding of the degree of potential surrounding the use of stem cells for treatment of corneal damage.
A team of researchers from the University of Cincinnati implanted human umbilical cord mesenchymal stem cells (UMSCs) which have the ability to become any of a wide range of adult cell types into mice corneas. The UMSCs survived in mouse corneas for three months with minimal signs of rejection and the findings from the study revealed that the UMSCs appeared to take on the properties of standard corneal cells called keratocytes and that the thickness and transparency of the animals' corneas improved significantly (it should be noted that full transparency was not restored; REFERENCE). This and other similar studies suggest that stem cells offer the potential to build new tissue-engineered corneal constructs which will lead to cures for both corneal blindness and visual impairment resulting from scarring following infection and trauma.
Cell therapies chase $4bn Wet AMD application in ophthalmic market opportunity
Diseases of the eye affect more than 30 million people worldwide and represent a market in excess of $20bn a year (SIDEBAR).
A University of Washington study on Blindness and Blinding Disease in the US (2004) noted that 13,000,000 Americans have signs of AMD, of which over 10,000,000 suffer visual loss and over 200,000 are legally blind from the disease. The occurrence of AMD increases with a patient's age and the study concluded that approximately 6,300,000 people are projected to develop AMD in 2030, compared to 1,700,000 in 1995.
Age related macular degeneration (AMD) represents a significant market opportunity given the size of the patient population and the lack of treatment alternatives.
Companies are targeting a therapeutic need to produce stem cells to benefit patients suffering from retinal degeneration caused by age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Both diseases are characterised by the death of critical photoreceptor cells caused rods and cones. Photoreceptor death is due to an abnormality and/or to disruption or death of supportive cells called retinal pigment epithelial (RPE) cells.
A small number of companies operating in the stem cell space are looking to exploit the significant commercial opportunities that exist for suitable treatments for AMD and some are planning to investigate using stem-cell based treatments for expanded ophthalmic applications. Our summary of some of the key players in this space is provided in Table 1.
Table 1 - Commercialization of Stem Cells for treatment of wet AMD
Current global market for drug treatments for Wet AMD is estimated to reach $4 billion by the end of 2010 (SIDEBAR)
There are 3 therapeutics and 2 treatment regimes on the market for treatment of Wet AMD. None of these restore lost vision, they only prevent additional loss of vision
â€¢Visudyne - Novartis
â€¢Lucentis - Genentech/Roche. For all of 2008, Lucentis sales increased 7%, totalling $875 million vs $815 million for 2007
â€¢Macugen - Pfizer
â€¢No current therapy is available for Dry AMD
Company + Products
Advanced Cell Technology
Retinal Pigment Epithelium ("RPE") Program
Advanced Cell Technology focuses on human embryonic and adult stem cell technology, with FDA approval to begin Phase 2 clinical trials for adult stem cell technologies, which are focused on cardiovascular disease and transplants. ACT has prepared its first IND aimed at AMD. Based on its preclinical studies to date, ACT filed its initial IND application in November 2009 utilizing their Retinal Pigment Epithelium ("RPE") Program for the treatment of macular degeneration. The treatment uses stem cells to re-create retinal pigment epithelium cells that support the photoreceptors needed for vision. RPE are often the first cells to die off in AMD, resulting in loss of vision.
University College London + Pfizer
British scientists have developed the world's first stem cell therapy for age-related macular degeneration (AMD). Under the new treatment, embryonic stem cells are transformed into replicas of the missing cells. They are then placed on an artificial membrane which is inserted in the back of the retina. Surgeons predict it will become a routine, one-hour procedure that will be generally available in six or seven years'time. The treatment involves replacing a layer of degenerated retinal cells with new ones created from embryonic stem cells. It was pioneered by scientists and surgeons from the Institute of Ophthalmology at University College London and Moorfields eye hospital.
In April 2009 Pfizer announced its financial backing to assist commercialisation and plans to manufacture the membranes essential for the treatment.
In November 2008, Pfizer decided to invest $100m in stem cell research, creating facilities in the US and UK, including hiring 70 scientists to staff the labs.
Lead product candidate, HuCNS-SC® cells
HuCNS-SC® cells are highly purified human neural stem cells which can be expanded and banked until they are delivered as patient doses.
Preclinical data - studies conducted with the Casey Eye Institute show that, when transplanted into the eye of the RCS (Royal College of Surgeons) rat (a well-established animal model of retinal degeneration), human neural stem cells protect the retina from progressive degeneration and preserve visual function long term as measured by two separate visual tests. The company states that the transplanted cells also exhibited robust, long-term protection of both rod and cone photoreceptors.
Preparing an IND
Focused on the use of a patients' blood or bone marrow-derived progenitor cells for the treatment of retinal disease. EyeCyte will employ the properties of these progenitor cells to treat Diabetic Retinopathy as its initial clinical target. Additional vascular and degenerative diseases of the eye will be pursued subsequently, including glaucoma and AMD.
CELL THERAPY IN NEUROLOGICAL DISORDERS
Targeting Multiple Sclerosis (MS)
Multiple sclerosis (MS) is an autoimmune disease in which the immune system attacks the central nervous system. In its early stages, the disease is characterized by intermittent neurological symptoms, called relapsing-remitting MS. During this time, the person will either fully or partially recover from the symptoms experienced during the attacks. Common symptoms are visual problems, fatigue, sensory changes, weakness or paralysis of limbs, tremors, lack of coordination, poor balance, bladder or bowel changes and psychological changes. Within 10 to 15 years after onset of the disease, most patients with this relapsing-remitting MS progress to a later stage called secondary progressive multiple sclerosis. In this stage, they experience a steady worsening of irreversible neurological damage.
Stem cell transplant reverses early-stage multiple sclerosis
In early 2009, Richard Burt and colleagues from Northwestern University's Feinberg School of Medicine reported the results of a small Phase I/II clinical trial investigating the effects of stem cell transplants in 21 patients aged 20 to 53 who had had relapsing-remitting multiple sclerosis. The disease had not responded to at least six months of treatment with interferon beta. The patients had also had MS for an average of five years.
The Feinberg School of Medicine team treated the MS patients with chemotherapy to destroy their immune system. They then injected the patients with their own immune stem cells, obtained from the patients' blood before the chemotherapy, to create a new immune system. The rationale behind this approach was to make the procedure much safer and less toxic than traditional chemotherapy for cancer. After the transplantation, the patient's new lymphocytes or immune cells are self-tolerant and do not attack the immune system.
The procedure called autologous non-myeloablative haematopoietic stem-cell transplantation appears to have reversed the neurological dysfunction of early-stage multiple sclerosis in the MS patients studied. Post-treatment the MS patients experienced improvements in areas in which they had been previously affected, including walking, ataxia, limb strength, vision and incontinence Patients who underwent the stem cell treatment continued to improve for up to 24 months after the transplantation procedure and then stabilized.
After an average follow-up of three years post-transplantation, 17 patients (81 percent) improved by at least one point on a disability scale. The disease also stabilized in all patients. Patients with late-stage MS do not benefit from the procedure.
Other targets for cellular therapy in neurological disorders where corporate activity has been noted are in potential treatments for amyotrophic lateral sclerosis, traumatic brain injury, stroke and Parkinson's disease.
1.4 million who sustain a TBI each year in the United States:
235,000 are hospitalized; and
1.1 million are treated and released from an emergency department.
The number of people with TBI who are not seen in an emergency department or who receive no care is unknown.
Direct medical costs and indirect costs such as lost productivity of TBI totaled an estimated $60 billion in the United States in 2000
Langlois JA, Rutland-Brown W, Thomas KE. Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths. Atlanta (GA): Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2006.
20 European countries. An aggregate hospitalized plus fatal TBI incidence rate of about 235 per 100,000 was derived. Prevalence rate data were not reported from any European country. An average mortality rate of about 15 per 100,000 and case fatality rate of about 11 per 100 were derived.
Acta Neurochir (Wien). 2006 Mar;148(3):255-68; discussion 268.
According to available statistics, 1.2 million people in Europe have Parkinson's: approximately 260,000 in Germany; 200,000 in Italy; 150,000 in Spain; 120,000 in UK and 117,000 in France.
USA - 1 in 272 people have Parkinson's disease, just in excess of 1 million people. In the United States, it is estimated that 60,000 new cases are diagnosed each year
The Numbers on ALS:
- The NIH estimates that 20,000 U.S. Americans have ALS and 5,000 are diagnosed
annually. The ALS Association estimates as many as 30,000 Americans have ALS, at an incidence of approximately 2 per 100,000, with 5,600 new diagnoses annually.
- BCLI reports there are 100,000 people with ALS in the western world alone at a cost of $1.25 billion in the U.S. and $3 billion for the western world.
- The average life expectancy is two to five years after diagnosis, although 10% survive 10+ years and 5% will survive 20+ years.
Table 2 - Commercialisation of cell and drug-based treatments for major neurological disorders
Company + Products
Brainstorm Cell Therapeutics
NurOwn - autologous bone marrow stem cells.
Current focus is to proceed to clinical trials for ALS application in 2010
Focus on generation of neuron-like cells and thus treatments for Parkinson's Disease, Amyotrophic Lateral Sclerosis (ALS) and spinal cord injuries.
Adult stem cell technologies
Develops autologous cell-based therapies for multiple sclerosis, rheumatoid arthritis and diabetes
Authorised to conduct a Phase II prospective trial designed to assess the safety and efficacy of autologous transplantation of human neural stem cell-derived dopaminergic cells into the affected striatal structures of 15 patients suffering from Parkinson's Disease.
Following an initial needle biopsy-harvesting of neural stem cells and a 6 to 9 months expansion process, cells are characterized and differentiated prior to unilateral injection in the putamen.
Amyotrophic Lateral Sclerosis - Filed IND
Traumatic Spinal Cord Injury - Preclinical
Ischemic Spastic Paraplegia - Preclinical
Huntington's Disease - Preclinical
Neural stem cells for use in ALS, traumatic spinal cord injury, paraplegia, Huntingdon'd disease.
The company's principal product candidate is its spinal cord stem cell line created with its Human Neural Stem Cell technology. The company's technology leverages the capabilities of foetal neural stem cells which it isolates from CNS tissue and then expands each cell in the laboratory up to 60 times ultimately creating a bank of billions of neural stem cells.
Stem Cell Therapeutics
NTx-265 for acute stroke
NTx-428 for traumatic brain injury (TBI)
NTx-488 for multiple sclerosis
Drug-based treatments to stimulate stem cells for treatment of a variety of neurological conditions
Stem Cells Inc.
proprietary HuCNS-SC®product candidate (purified human neural stem cells)
January 2009 - completed Phase I clinical trial of HuCNS-SC cells in Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten's Disease, a brain disorder in children. Data from this study on;y demonstrated the clinical safety and tolerability of the cells.
November 2009 - company initiated with the University of California, San Francisco (UCSF) Children's Hospital, a Phase I clinical trial to evaluate the therapeutic potential of StemCells' to treat Pelizaeus-Merzbacher Disease ( PMD), a myelination disorder that primarily affects infants and young children. In this trial, patients with a fatal form of PMD will be transplanted with the Company's HuCNS-SC cells to evaluate safety and toexplore the ability of the cells to myelinate the patients' nerve axons .
Stem Cells Inc., plans to treat neurological, liver and pancreatic conditions with stem cell technology. The conditions they are directly seeking cell therapies for are liver disease, diabetes, Neuronal Ceroid Lipofuscinosis (Batten disease), ALS, disorders of CNS myelination, spinal cord indications, wet AMD, Alzheimer's Disease.
StemCells Inc. also sees potential for its technology in the use of HuCNS-SC for high throughput screening of drug targets, toxicology studies in drug development and gene expression profiling
Transformation of skin cells directly to nerves
Dr Marius Wernig and his group at the Institute for Stem Cell Biology and Regenerative Medicine at Stanford have recently published a paper in Nature in which they describe work confirming their theory that, under the right conditions, a combination of transcription factors could be identified which would allow them to convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro. Wernig and his team showed that a combination of only three neural-lineage-specific transcription factors, namely Ascl1, Brn2 (also called Pou3f2) and Myt1l facilitated the conversion of ordinary mouse skin cells to fully functioning induced neuronals which expressed multiple neuron-specific proteins, generated action potentials and formed functional synapses.
Attempts to reproduce the experiment using human cells is proving to be trickier, as might have been anticipated and the induced neuronal cells have been found to have a shorter lifespan than the more primitive stem cells and do not proliferate well. However, this finding adds positively to the belief that identifying and selecting appropriate combinations of transcription factor cocktails could allow researchers to manipulate nuclear reprogramming and transform skin cells into all cell types. Furthermore Wernig sees potential to bypass transcription factors and search for small molecules or methods to activate the cells. An example of where this might be beneficial, cited by Wernig, is when someone suffers a stroke or other brain lesion, it is known that occasionally this leads to an overproliferation of glial cells in the brain. In such circumstances it would be extremely useful clinically to convert those glial cells into neurons.
Nature advance online publication 27 January 2010
Direct conversion of fibroblasts to functional neurons by defined factors Thomas Vierbuchen1,2, Austin Ostermeier1,2, Zhiping P. Pang3, Yuko Kokubu1, Thomas C. Südhof3,4 & Marius Wernig1,2
CELL THERAPY IN CARDIOLOGY
The potential of cell transplantation to repair damaged myocardium is attractive and has been widely studied in both experimental and clinical conditions using various cell types. The quest for the ideal cell is still ongoing, as the attributes of the ideal cell and the working mechanism of cell regeneration still remain to be defined.
According to the American Heart Association 2007 Statistical Update, there were approximately 865,000 cases of acute myocardial infarction (AMI) that occurred in the US in 2004 and approximately 7.9m individuals living in the US that had previously suffered a heart attack. In addition there were more than 452,000 deaths that occurred from various forms of ischaemic heart disease, and 156,000 deaths due directly to myocardial infarction in 2004.
The World Health Report of 2003 published by WHO, contained estimates that of the 16.7m deaths from cardiovascular diseases every year, 7.2m are due to ischaemic heart disease, 5.5m to cerebrovascular disease, and an additional 3.9m to hypertensive and other heart conditions. This particular report also highlighted that a sizeable proportion of the 20m people who survive heart attacks and strokes every year need to receive clinical care which may involve drug or device treatments, all of which ultimately place considerable financial burdens on healthcare systems.
Current drug treatment for heart disease include beta-blockers, diuretics, angiotensin-converting enzyme (ACE) inhibitors and statins. Surgical treatment options include the implanting of assistive devices such as pacemakers or defibrillators. In those individuals where the implantation of mechanical ventricular assist devices has been necessary, long term improvement in heart function is observed but the downside to this is the need to all too frequently address complications such as infection and blood clotting.
Ultimately,neither drug or device treatments restore function to damaged tissue. Hence there is an unmet need which could be addressed by cell therapies which can repair or regenerate myocardial tissue.
Mesenchymal stem cells show promise in cardiology cell therapy applications
Ischemic heart failure occurs when cardiac tissue is deprived of oxygen. When the ischemic insult is severe enough to cause the loss of critical amounts of cardiac muscle cells (cardiomyocytes), this loss initiates a cascade of detrimental events, including formation of a non-contractile scar, ventricular wall thinning, an overload of blood flow and pressure, ventricular remodeling (the overstretching of viable cardiac cells to sustain cardiac output), heart failure, and eventual death.4 Restoring damaged heart muscle tissue, through repair or regeneration, therefore represents a fundamental mechanistic strategy to treat heart failure.
A consensus seems to have built up amongst researchers that, among the cells effective in the treatment of heart disease, autologous, non-embryonic cells which do not require culturing to obtain a therapeutic dose and can be administered during the same procedure may be logistically easiest to use. These cell types may have wider application in catheterisation laboratories. The most extensively studied and characterised cells that have been shown to have some of the above mentioned ideal properties are mesenchymal stem cells (MSCs). MSCs are multipotent, adult stem cells that can expand in cell culture and demonstrate the ability to differentiate into multiple cell phenotypes including vascular endothelia cells and cardiomyocytes as well as bone, cartilage, neuronal and skeletal muscle progenitor cells.
Many previous cell therapy trials in patients with AMI have been using mononucleated bone marrow derived cells (BMCs) that consist of a heterogeneous cell population. A small number of these unfractioned BMCs are MSCs. Results of these trials showed an improvement of regional wall motion, global ejection fraction and, in some cases, a reduction of infarct size in the treated group.
Recently it has been shown that adipose tissue, in addition to committed adipogenic, endothelial progenitor cells and pluripotent vascular progenitor cells, also contains multipotent cell types.
The importance of this development is significant because, in contrast to bone marrow, adipose tissue can be easily and safely harvested in large quantities and with minimal morbidity regardless of the condition of the patient, making it an appealing source for cell therapy. Adipose derived stem cells (ADSCs) are a cell population with properties that are very similar, though not identical, to those of marrow-derived MSCs. These cells have extensive proliferation capacity and are able to differentiate (in cell culture conditions) into osteogenic, chondrogenic, myogenic and neurogenic lineages.
Table 3 - Commercialisation of cell and drug-based treatments for cardiology
Company + Products
Autologous cell products using the company's Tissue Repair Cell (TRC) technology to harvest bone marrow as source of progenitor and stem cells
Stem cells for use in cardiac and vascular tissue regeneration
Advanced Cell Technology
Phase II clinical trials
Human embryonic and adult stem cells focused on cardiovascular disease and transplants
Collaboration with Angiotech Pharma to develop MultiStem
Focus on myocardial infarction, peripheral vascular disease and strokes in addition to stem cell transplantation.
MyoCell - muscle-derived stem cell therapy to restore heart function
Cardiovascular disease and heart failure
Autologous adult stem cells from bone marrow
Prochymal - Phase III clinical trials for Graft vs Host Disease (GvHD) and Crohn's Disease. Trials suspended
Prochymal - heart attack. Uncertainty around this programme.
Prochymal - diabetes
Chondrogen - Phase I/II for pain/arthritis of the knee
Adult stem cells from bone marrow for cardiovascular, diabetes, Crohn's Disease and GvHD
ReNeuron Group PLC
ReN001 - adult stem cells for stroke. In 2009 ReN001 therapy for stroke has received both UK regulatory and conditional ethical approvals for a first-in-man clinical study
Cellular therapy for Stroke patients.
The company, based in Thailand, develops stem cell treatments for patients with coronary artery disease and congestive heart failure
CELL THERAPY IN ORTHOPAEDICS
Commercialisation of stem cell therapies for orthopaedic applications
Company + Products
Regenerative medicine combination device/cell-based therapies for orthopaedic/spine, sports medicine and dental applications
Human embryonic stem cell product, GRNOPC1 - Phase I clinical trials commenced in January 2009
Acute spinal cord injuries
Replicart - Phase II clinical trial for knee osteoarthritis
Adult stem cells for bone and cartilage repair and regeneration. Also has a US subsidiary, Angioblast, focused on cardiovascular applications
Development of human neural stem cells, HuCNS-SC and liver engrafting cells (hLEC)
Focus on spinal cord injuries, myelination and retinal disorders
CELL THERAPY IN PERIPHERAL VASCULAR DISEASE
Commercialisation of stem cell therapies for vascular applications
Company + Products
Peripheral vascular disease
Allogeneic products developed from human placenta.
Also PLX-IBD for inflammatory bowel disease,
PLX-MS - multiple sclerosis
PLX-BMT - bone marrow transplants
PLX-STROKE - ischaemic stroke
Multiple, including peripheral arterial disease, GI complications, neurodegenerative and cardiovascular
ReNeuron Group PLC
ReN009 -ReNeuron is developing its ReN009 therapy as a non-patient specific stem cell treatment for late-stage PAD, or critical limb ischaemia, in diabetic patients for whom PAD is a side-effect of their diabetes.
Cellular therapy for PAD patients.
Keep hope alive - the ideas keep coming
Stem Cell therapy + Vaccination - targeting aggressive cancers
In August 2009 a team of Harvard scientists led by Vincent Ho at the Dana-Farber Cancer Institute treated patients suffering from chemotherapy resistant acute myeloid leukemia (AML) with an immune system-stimulating vaccine 30-45 days after a stem cell transplant. The timing of the administration of vaccine was seen to be critical to the success of the combinatorial immunotherapeutic protocol.
In the study, twenty-four AML patients firstly received chemotherapy to reduce the number of diseased hematopoietic cells in their bone marrow. After the course of chemotherapy the patients received an infusion of healthy hematopoietic stem cells from a matched donor. The transplanted cells settled in the patient bone marrow, where they began to regenerate the individual's blood supply, including white blood cells and other agents that constitute the immune system.
Between 30 and 45 days after transplant, 15 of the patients began receiving a cancer vaccine. The administered vaccine was made by surgically removing cancerous or myelodysplasic tissue from patients and genetically altering the diseased cells so they would produce the protein called GM-CSF (garnulocyte/monocyte - colony stimulating factor.).
Ten of the participating patients completed the full course of six vaccinations. Of the 10 who received the entire vaccine course, nine remain alive today and are currently in full remission up to four years after treatment. This is a highly encouraging result because it is documented that historically only about 20 percent of similar high-risk AML and myelodysplasia patients who receive a transplant have a life expectancy of perhaps two years.
A further positive outcome of the treatment was the observation that rates of graft versus host disease in the patient cohort were no higher than with stem cell transplants alone. Together, the results from the study suggest that oncologists may be able to safely combine treatments which involve cell therapies to replenish diseased cells with health cells while stimulating the immune systems of patients with relevant vaccines and ultimately strengthen the cancer treatments available for a host of malignancies.
Biologic activity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic stem cell transplantation
Mesenchymal Stem Cells and Advanced Wound Care
Jin et al report in Artificial Organs (2008 Dec; 32(12):925-31) the use of bone marrow-derived mesenchymal stem cells seeded onto a collagen-GAG scaffolding matrix to form a dermal patch, which when applied to a deep dermal partial thickness burn (heated brass contact injury at 100°C for 20 seconds) on porcine skin showed significantly better healing, keratinization, wound contraction and increased vascularization over standard treatment protocols. Jin et al believe that tissue engineered "skin" using bone marrow-derived MSCs can accelerate wound healing in a suitable device matrix could lead to advances in wound care and graft therapy for burn victims.