Regenerative medicine: enhance cell bioprocessing through cell-based combinatorial culture
Regenerative medicine has emerged as one of the major areas of modern medical therapy. Its primary objective is to restore or establish normal function through the regeneration or replacement of diseased cells, tissues or entire organs. There are a variety of methods and approaches by which this can be achieved. These techniques include cell and gene therapy, tissue engineering or regenerative drug therapy.
There have been a number of key innovations in the field of regenerative medicine. Allogeneic transplantation of bone marrow haematopoietic stem cells (HSCs) was the pioneering regenerative medicine therapy. It can be used both to replace blood stem cells and to reconstitute the full blood lineage spectrum. The therapy has stood the test of time and is established as a gold standard in healthcare for many haematological disorders, decades after its introduction into the realms of therapy. However, despite all the developments to date, there remains a number of serious limitations to allogeneic transplantation of bone marrow. One issue is a discrepancy between supply and demand. This is caused by a number of significant factors including a shortage of bone marrow donors, the cell volumes required per transplantation and a degree of uncertainty over whether existing stocks of frozen umbilical cord blood cells can meet current and future demand.
Another challenge is the need to match human leukocyte antigen (HLA) groups between donors and recipients, avoiding any prospect of transplant rejection. This problem is solved through the use of umbilical cord blood, a more primitive form of blood cell than bone marrow and, consequently, less requiring of exact donor-recipient HLA matching. The use of ex vivo expansion to boost HSC numbers prior to transplantation shows tremendous promise. However, existing methods of HSC expansion remain relatively inefficient and expensive as a result of their reliance on costly cytokines.
As a consequence of discovering human pluripotent stem cells (hPSCs) – including both human embryonic stem cells (hESCs) and induced pluripotent ones (iPSCs) – is the creation of another viable source of cells that will meet future demand through their ability to expand almost indefinitely within in vitro culture. Moreover, their ability to differentiate into any somatic cell (a quality known as pluripotency) opens up the potential to develop cellular therapies for a range of diseases for which there is no cure at present. This includes diabetes, Parkinson’s disease, and age-related macular degeneration. In addition, this approach provides a defined and scalable method that generates rare progenitor cell types and which can be further used for the discovery of regenerative drugs with a capacity to stimulate tissue regeneration in vivo. However, these cells require in vitro expansion and differentiation to direct them to their target cell or lineage of interest to fulfil therapeutic potential, as a direct consequence of the valid safety concerns that remain over the direct transplantation of hPSCs. Current strategies that have been adopted to bring this about are inefficient and costly.
A major development in the regenerative medicine field has been the emergence of cellular gene therapies targeting a wide range of disorders – predominantly oncological in nature. Whilst these have, to date, mostly been limited to blood cancers, the leading players in the industry remain optimistic that these therapies will eventually be able to treat solid tumours in the future.
There are two particularly promising therapeutic strategies in this field. One is engineering T-cells and the other is the gene editing of diseased cells in patients suffering from genetic disorders – utilising a combination of traditional viral vectors and novel gene editing tools such as CRISPR/Cas9. Engineering T cells grabbed the headlines last year due to the outstanding efficacy of one such therapy, Kymriah. This was developed through a collaboration between Novartis and the University of Pennsylvania which resulted in the pioneering FDA approval for the treatment of the B cell precursor, ALL. A major cause of concern, however, with autologous therapies is that diseased tissue from the patient subjected to the manufacturing process will often expand inefficiently compared with the cell line or tissue used to develop the process. Let’s take gene editing as a prime example. There was considerable excitement following the approval of Strimvelis, a gene therapy product for the treatment of ADA-SCID, recently purchased by Orchard Therapeutics as part of a large-scale acquisition of GSK’s rare disease programme – leading the way for a host of therapeutic programmes looking at rare genetic diseases for which there is no current cure at present. The problem however with such therapies, which are mostly autologous, is that manufacturing processes for such technologies remain expensive, with the consequent effect of higher costs being passed on to healthcare systems. Moreover, the use of autologous tissue also raises a similar prospect of process variability to that discussed previously.
Cell-Based Combinatorial Screening – how it functions
To exploit the capabilities of such cells for use in regenerative medicine and drug discovery, we must, in the case of stem cells, be able to direct their differentiation and promote their expansion in vitro in a manner that is reproducible, cost-effective and efficient. This challenge has been directly addressed through the development of cell-based combinatorial screening technology, leading to the rapid and efficient identification of optimised protocols for cell expansion and cell differentiation, as well as providing human cells for use in drug discovery. This technique is capable of simultaneously testing thousands of combinations of cell culture variables through miniaturising and multiplexing large numbers of stepwise cell culture experiments, massively increasing throughput.
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