Summary
A framework to optimise the use of stem cell therapies through research and development should be an integral part of a nationally organized unrelated donor blood stem cell program. Such a program is also required to maintain the UK’s leadership position in stem cell therapy and biology for the benefit of patients and the economy.
Unrelated Blood Stem Cell Transplantation
Human stem cells can be derived from three major sources: embryos, umbilical cord blood and adult tissues. Adult blood stem cells isolated from bone marrow of siblings of patients have been successfully used in transplantation to save lives of patients with blood cancers for over 40 years. More recently, umbilical cord blood stem cells and stem cells from unrelated donors have been successfully transplanted to treat patients without a sibling donor. In addition, the UK has also led efforts to exploit the enormous health care potential of novel stem cell-based therapies for serious diseases where limited, or no, treatment options are currently available.
The number of unrelated donor stem cell transplants has increased steadily in the UK over recent years (Annex 1). This increasing activity is mirrored in Europe. Although unrelated donor HSCT is a proven life-saving therapy, it is expensive and associated with considerable morbidity: 40-60% of patients still die after transplant. The optimal indications for HSCT and methods to deliver the transplant still need to be refined. This is not surprising as it is a complex treatment that is still being developed. Thus, there is a strong rationale for an integrated Research and Development program to reduce the cost of, and improve patient outcomes from, unrelated donor HSCT.
Cord Blood Stem Cells for Discovery Research
Enormous opportunities exist for discovery research to develop innovative future therapies for blood diseases and more broadly, for a much larger population, that suffers from common degenerative diseases such as Alzheimer’s and Parkinson’s diseases, paralysis due to spinal cord injury, heart failure, liver disease, and Type I diabetes (Table 33). A human is able to regenerate some tissues. For example, blood and skin are continuously restored, and bone, muscle, liver, and blood vessels have a limited self-renewal capacity. However, other tissues (e.g. joints or the brain) are not easily repaired after trauma or disease. Although many drugs alleviate symptoms, most fail to restore normal function to damaged tissue. Replacing a damaged organ with a donor organ is not always possible, is expensive and often associated with morbidity and mortality. Stem cell-based therapies offer the potential for cure. Some estimates, suggest a $30 billion market for cell-based therapies, the majority of which could be based on blood stem cells.
Table 33 Indications that may benefit from blood/bone marrow derived stem cell-based therapies
Indication U.S. Patient Population
Myocardial infarction 7.2 million Congestive heart failure 5 million
Stroke 5.5 million
Type I Diabetes 2 million Osteoarthritis 43 million Alzheimer’s disease 4.5 million Parkinson’s disease 1 million Spinal cord injuries 0.25 million Hematopoietic stem cell transplants 18 thousand
Cord blood stem cells offer an easily-accessible stem cell source to study basic and translational stem cell biology to provide novel drug and/or cell-based therapy to restore normal organ function either by stimulating endogenous stem cells or providing exogenous stem cells. Stem cell research has attracted academic research funding (both Government and charitable sectors). The UK is a world leader in stem cell science with
internationally competitive University based programs in Oxford, Cambridge, London and Newcastle. However, the science is still immature and not helped by poor access to high quality stem cells for research. There is interest from commercial biopharma and biotech but this is more prominent in the US. Few UK-based stem cell based companies exist and the structure to interface with UK-based scientists needs development. Despite this, clear opportunities for commercial exploitation of cord blood stem cells exist and this Review provides a timely opportunity to facilitate UK-based discovery stem cell research and integrate it with private commercial ventures and clinical Centres of Excellence that can conduct clinical trials of stem cell therapies.
Examples of Key Research and Development Opportunities
Clinical Studies To Optimize Cord Blood Stem Cell Transplantation (Figure 44)
1. Establishing a comprehensive national registry to collect clinical outcome and health economic data on unrelated donor blood transplants. This is critical to ensure uniform best practice and collect cost-benefit data on unrelated donor HSCT.
2. Establishing national clinical trials of unrelated donor HSCT to test the indications and methods on how to best to deliver expensive and complex transplants. This would also allow for uniform data sets that facilitate evaluation of best practice.
Figure 44 Expanding clinical transplant capability
Clinical Research Unit
Clinical units
Registration of all transplants Web-based data collection: procedure outcome, quality of life, health economic
data.
Monitor and set practice – nationally agreed protocols – uniform data sets.
Implementation of best practice
Clinical trial portfolio Phase I/II; Phase III – linked to national
disease trial groups Biological /translational studies – characterise immune effector response,
haemopoietic stem and progenitor content
Sample collection from cohorts
Scientific labs with appropriate technology and
interests in translational questions
Expanding clinical transplant research capability
Translational and Clinical Research (Figure 45)
1. The outcome of transplantation depends on stem cells and the cells they generate (progenitor cells) being able to reconstitute normal blood cells. Thus, it is important to prospectively characterize the number and function of stem and progenitor cells in donor stem collections that are stored and those that are transplanted.
2. The outcome of HSCT also depends on transplanted stem and progenitor cells generating immune cells capable of recognizing and destroying patient’s cancer cells. Thus, it is important to prospectively characterize the number and function of immune effector cells in stem blood collections that are stored and those that are transplanted.
3. Clinical trials need to have attached biological studies to explore of the use of cord blood stem cells in regenerative medicine. An example would be to explore stem cell therapy for degenerative joint disease, which affects circa 10% of the UK population. In early stages of degenerative knee joint disease cartilage at articular surfaces is defective. One operation currently performed routinely in the NHS is to abrade the cartilage to release bone marrow cells, which transform to fibrocartilage to provide a useful repair. However, this crude repair only lasts for only 3-6 years and is only effective in a proportion of patients. An important question in the field would be to define stem cell populations that would be more effective at cartilage formation without forming the fibrous tissue that compromises repair.
Figure 45 Delivering a translational research strategy
Translational programs in transplantation
Clinical units Translational labs
Basic stem cell and immunology
labs
Partnership facilitated by appropriate funding programs
Delivering a translational research strategy
Collaboration with industry
Basic Science Research (Figure 46)
1. In adults, the number of stem cells in a standard cord blood collection is often too small and transplants regularly require two cord blood stem cell collections. This doubles the cost of cord blood procurement.Thus, there is an opportunity to reduce cost by developing ex-vivo cord blood stem/progenitor expansion protocols. This work is still in its infancy with few, if any, molecules shown to provide true stem cell expansion.
2. There is an opportunity to discover new molecules that direct the differentiation of cord blood stem cells into non-blood cells such as neurons and musculoskeletal cells. This would greatly enhance the prospect of regenerative therapy.
Figure 46 Developingnew stem cell and immune cell based therapeutics
Scientific programs in stem and immune cell
Clinical units Translational labs
Basic stem cell and immunology
labs
Partnership facilitated by appropriate funding programs
Developing new stem and immune cell based therapeutics
Collaboration with industry Collaboration with other academic funders
Sale of Cord Blood Stem Cells for Academic and Commercial Research
There is a demand for cord blood stem cells for research into pathways involved in diseases with the aim of identifying of new drug targets. These new drugs could be either be small molecule or biological drugs that bind key targets to block the pathological pathways, or ultimately could be stem cells themselves that replace a lost function in the disease. Sale of high quality cord blood stem cells from cord blood collections that are too small for transplantation would generate additional revenue. Intellectual property on the novel drug targets could be generated from such research.
Securing Cord Blood Stem Cell Research and Development
Governance
We recommend an oversight committee that would include national/international clinical and scientific experts, health economists, lay representation and representatives from industry. The creation of such a committee could be the remit of the UK Stem Cell Strategic Forum. This committee would issue calls for R&D proposals and/or set aside some funds for response mode funding. Funding would be granted subject to peer review. The committee would produce annual reports of funds spent and outcomes produced.
Research and Development Funding
We recommend that the oversight committee be charged with securing funding. Funding sources could include savings made from procurement and delivery of unrelated donor stem cell transplantation and sale of cord blood stem cells for research. No additional Government money would be required. In addition, the committee should approach key stakeholders such as NHS Blood and Transplant, the National Institute for Heath and Research, the Medical Research Council, large medical charities, Anthony Nolan Trust, the Wellcome Trust, the British Heart Foundation, Arthritis Research UK and directed philanthropic donations should be invited. Different stakeholders mentioned above may wish to support select opportunities that address the concerns of their constituencies. Support should be sought from industry. We recommend that working with Regional Centres of Excellence in Alternative Donor Transplantation the oversight committee should facilitate the development of early and late phase trials in unrelated donor transplantation and build links between the UK’s world class science base in stem biology and an integrated clinical trials network.
Liaison with Industry
We recommend a dedicated technology transfer arm is created by the oversight committee to liaise with industry to define research opportunities and commercialise intellectual property arising from stem cell research: including patenting, licensing, and even creating spin-out companies.The technology transfer team would also work with UK academics to allow industry access to experts from the UK’s stem cell world-class, clinical and translational research base and forge agreements on use of stem cells, derivatives or related technologies in clinical practice. Finally this team would be responsible for marketing and encouraging access by clinically-focused biotech and pharma companies.