Background on Stem Cells
The human body contains approximately 210 types of cells, each of which performs a specific function, depending upon its location. For example, red blood cells carry oxygen and neurons transmit nerve impulses.
Stem cells are the primitive precursors to these more mature cells and have the potential to:
- reproduce themselves; and
- differentiate into tissue-specific cells, such as the types described above.
There are many different types of stem cell, and they vary in their abilities to reproduce themselves and differentiate. However, they can be broadly categorised into two major groupings, being pluripotent and adult stem cells. The characteristics of these two groups of stems cells are described further below, and further details on the different types of stem cells can be found in the Frequently Asked Questions section of this website.
Pluripotent Stem Cells:
Pluripotent stem cells are the most versatile cells of all, having the ability to reproduce themselves indefinitely, and also differentiate into any other type of cell in the body. There are two main types of pluripotent stem cell, being embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs).
ESCs are isolated from five to seven day-old embryos donated with consent by patients who have completed in vitro fertilisation therapy, and have surplus embryos. The first human ESCs were isolated by Professor James Thomson at the University of Wisconsin-Madison in 1998 (one of the inventors of the Cymerus™ technology). The use of ESCs has been hindered to some extent by ethical concerns about the extraction of cells from human embryos.
iPSCs are a man-made version of ESCs, derived from adult cells. iPSCs have very similar characteristics to ESCs, but avoid the ethical concerns described above, since they are not derived from embryos. Professor Thomson and his team, including Professor Igor Slukvin (one of the founders of Cynata) were also pioneers in the development of iPSCs. In 2007, they were one of two independent research groups that first reported the creation of iPSCs from human cells (along with Professor Shinya Yamanaka et al, at Kyoto University, Japan). iPSCs are typically derived from fully differentiated adult cells that have been reprogrammed back to a pluripotent state.
This ability to reprogram cells from adult donors into a pluripotent embryonic-like state has been met with great excitement, as it significantly advanced the potential for regenerative therapy. iPSCs – like ESCs – are cells that can (i) be expanded without limit, (ii) can be stored over long periods and (iii) can produce tissue cells of any type. This makes iPSCs an ideal building-block for cell-based therapies.
iPSCs themselves are not administered directly to patients as medical treatments. Instead, the iPSCs are used as a starting material to produce other types of cells, which may have the potential to be used as therapeutic agents. Recent approval in Japan of a study involving iPSC-derived retinal pigment epithelium cells in patients with eye disease demonstrates a preparedness of regulatory agencies to accept pre-clinical safety testing and approve clinical studies of iPSC-derived cells.
Mesenchymal Stem Cells:
The most widely studied type of adult stem cells are known as mesenchymal stem (or stromal) cells, or simply MSCs.
MSCs are found in a wide range of human tissues, including bone marrow, adipose tissue (fat), placenta and umbilical cord blood. There has been extensive interest in the development of MSCs as therapeutic products, in particular because of their ability to modulate the immune system. They also secrete bioactive molecules such as cytokines, chemokines and growth factors, which has resulted in these cells being dubbed “drug factories” or “medicine secreting cells”.
MSCs can be either autologous or allogeneic. Autologous means a patient is treated with their own cells, while allogeneic means that cells from a donor are used to treat other people. Allogeneic MSCs have not been shown to cause immune reactions in other people, so they can be used in an “off the shelf” manner, without any requirement for matching the donor to the recipient. This has important commercial advantages, so biotechnology companies have largely focussed on allogeneic rather than autologous MSCs.
MSCs have been shown to facilitate regeneration and effects on the immune system without relying upon engraftment – in other words, the MSCs themselves do not become incorporated into the host, rather they exert their effects and are then eliminated within a short period of time.
There are currently over 600 ongoing human, clinical trials, in which MSCs are being used to treat a very wide range of medical conditions, including heart disorders, diabetes, orthopaedic conditions, and autoimmune diseases, among others.
First Generation Methods of MSC Manufacture:
Unlike Cynata’s Cymerus™ technology, first generation methods to manufacture MSC-based products rely on the isolation of MSCs from donated tissue (for example bone marrow, fat or placenta), followed by “culture expansion”. When cells are culture expanded, the total number of cells increases as a result of a process called cell division. Thus, one cell gives rise to two, then two to four, and so on.
The difficulty with this approach, using MSCs derived from donor tissue, is:
(i) In practice, MSCs start to change as culture expansion progresses. This can result in the cells losing potency, and ultimately they stop dividing altogether (this is known as “senescence”).
(ii) Only a relatively small number of cells can be isolated from each donation – for example a bone marrow donation typically yields fewer than 20,000 MSCs, while a clinical dose is typically more than 100 million MSCs.
This means that each tissue donation can produce only a limited number of MSC doses, so a continuous supply of new donors would be needed to facilitate manufacturing at commercial scale.
There are significant logistical challenges and costs associated with collecting tissue donations. Firstly, it is likely to be difficult to find sufficient numbers of suitable donors to meet large scale commercial demand, particularly with donation procedures that are potentially risky, painful and invasive such as bone marrow harvesting. Secondly, the process of screening and testing multiple donors, followed by collecting and testing the donated material, is both time consuming and expensive.
Another problem with relying on a continuous supply of new donors is that changing the starting material is likely to change the characteristics of the end product – it has been shown that the number and quality of MSCs that can be isolated from different donations varies substantially. With biological products, when the starting material is changed, regulatory authorities require evidence of “comparability”, which means proof that the final product does not change. Comparability testing with this type of product is a very complex, time consuming and costly process, and successful demonstration of comparability is far from guaranteed. In the event that comparability testing fails, the MSCs manufactured from the new donation would be classified as a different product, and commercial supply that new product would not be permitted under the regulatory approval for the original product.
Consequently, it is extremely expensive to manufacture MSC products using processes that rely on a continuous supply of tissue donations, and there is a significant risk of supply constraint or interruption.