Background and Explanation of Terminology
What is Cynata's Cymerus™ technology?
The trademark Cymerus™ refers to the patented process of generating cell-based products from intermediate cells, known as mesenchymoangioblasts (MCAs), which in turn are derived from induced pluripotent stem cells (iPSCs). This technology was originally developed at the University of Wisconsin-Madison, WI, USA.
At present, Cynata is focussed on the production of mesenchymal stem cell (MSC)-based products using the Cymerus™ technology.
What are mesenchymal stem (stromal) cells or MSCs?
Mesenchymal stem cells, also known as mesenchymal stromal cells or MSCs, are a particular type of stem cell 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 to 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.
What are mesenchymoangioblasts or MCAs?
Cynata’s Cymerus™ platform stem cell technology is based upon extremely important and versatile stem cells known as mesenchymoangioblasts (MCAs). MCAs are precursors to mesenchymal stem cells (MSCs). Cynata’s proprietary technology utilises induced pluripotent stem cells (iPSCs) originating from an adult donor as the starting material for generating MCAs, and in turn for manufacturing the MSC therapeutic product.
What are pluripotent stem cells/iPSCs?
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: 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 investors 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 into a pluripotent state.
Cynata uses iPSCs as a starting material in its Cymerus™ process, and has secured a clinical grade human iPSC line manufactured by Cellular Dynamics International (CDI; Nasdaq: ICEL). Unlike early methods of iPSC production, the iPSCs that Cynata uses were produced without the use of viruses and without changing the cells’ DNA. Therefore, these iPSCs are well-suited to the manufacture of products for human use.
Are there different ways of producing iPSCs? What method was used to produce Cynata's iPSCs?
Yes, there are a number of different ways of producing iPSCs, which are often described as “reprogramming methods”. It is important to be aware of the distinction between different reprogramming methods, as studies conducted on iPSCs produced by first generation methods are generally not relevant to iPSCs produced using more recent technology.
First generation reprogramming methods involved the use of viruses that inserted particular genes into the donated cells’ DNA – a type of genetic modification. However, such reprogramming methods were never considered to be suitable for the manufacture of products for human use, because of the risk of genetic mutations (this is known as “insertional mutagenesis”). Furthermore, when reprogramming genes persist in cells, they contribute to genetic instability and aberrations. These limitations were acknowledged in the original publication of the method to produce human iPSCs by the group at the University of Wisconsin-Madison (UWM).
To address this problem, the team at UWM developed “non-integrating episomal” reprogramming methods. These methods use plasmids, which are short segments of DNA that do not integrate into the donated cells’ DNA, and consequently avoid the risks associated with insertional mutagenesis and persistence of reprogramming genes.
There is a growing body of evidence demonstrating that iPSCs produced in this way are not associated with the same problems as iPSCs produced using first generation methods. For example, scientists at Johns Hopkins University conducted a study of iPSCs generated by non-integrating episomal methods, using highly sensitive “deep whole genome sequencing” analyses, which was published in Cell Stem Cell. This study confirmed that the episomal DNA could not be detected in the iPSC lines (i.e. the plasmids did not integrate or persist in the reprogrammed cells), that it did not alter the structure of the cells’ DNA and that these reprogramming methods are not inherently mutagenic. Similarly, a recent comparison of reprogramming methods published in Nature Biotechnology by a group of scientists from Harvard University concluded that episomal reprogramming “seems particularly well-suited for clinical translation because it is integration-free, works reliably with patient fibroblasts and blood cells, and is based on a very simple reagent (plasmid DNA) that can easily be generated using current good manufacturing practice (cGMP)-compatible processes”.
Cynata’s iPSCs were manufactured by Cellular Dynamics International (CDI; Nasdaq: ICEL), using a non-integrating episomal reprogramming method based on that originally developed at UWM. Additionally, Cynata’s iPSCs were derived from a fully consented donor, in compliance with the FDA’s GMP requirements.
Why are iPSCs important for regenerative medicine?
This ability to reprogram cells from adult donors into a pluripotent embryonic-like state has been met with great excitement, as it has significantly advanced the potential for regenerative therapy. iPSCs have similar characteristics to ESCs, without the ethical issues. The discovery is a generational advancement in processes that require repeat donor-derived materials.
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.
Are iPSCs safe for human use?
It is important to understand that iPSCs themselves are not administered to patients. Instead, the iPSCs are used as a starting material to produce other types of cells, such as MSCs in Cynata’s case. Cynata’s Cymerus™ technology includes attributes designed to eliminate iPSCs early during the manufacturing process. Cynata’s final product contains only MSCs, which have similar characteristics to MSCs isolated from tissue donations (e.g. bone marrow).
A number of organisations around the world are currently developing iPSC-derived cellular therapies for human use. Cynata has received regulatory approval in the UK and Australia to commence a Phase 1 clinical trial in GvHD. The approval of this trial was important, as it demonstrated that regulatory authorities and ethics committees are comfortable with the concept of using iPSC-derived cells in humans.
Does Cynata use embryonic stem cells?
No, Cynata uses induced pluripotent stem cells, or iPSCs, as a starting material in its manufacturing process. iPSCs are derived from cells obtained from an adult human donor.