Research Field Cell & gene therapy

Pulling Back the Curtain: Combinatorial Screening

The regenerative medicine field is relatively new – where do you see its potential?

Whereas traditional pharmaceutical and biotechnology companies have focused on using small molecules and proteins, respectively, to target specific molecular pathways within cells, regenerative medicine aims to develop cures for diseases rather than manage symptoms. For example, pluripotent stem cells may be able to regenerate retinal pigmented epithelial cells lost during age-related macular degeneration or dopaminergic neurons destroyed by Parkinson’s disease. Regenerative medicine can also improve the performance of immune cells unable to cope with aggressive diseases, such as certain cancers. A recent, highly publicised example has been the unprecedented efficacy of CAR-T therapies in fighting blood cancers, such as acute lymphoblastic leukemia. Furthermore, where a disease is clearly defined as being caused by a specific genetic defect, novel gene-editing technologies are able to permanently correct these defects either ex vivo or directly within the patients themselves.

What is combinatorial screening technology?

To exploit the capabilities of cells for use in regenerative medicine we must be able to direct their differentiation (in the case of stem cells), and/or promote their expansion in vitro in a manner that is efficient, reproducible and cost effective. We developed combinatorial screening technology – Combicult – to directly confront this challenge, leading to rapid and efficient identification of optimized protocols for cell expansion and differentiation, as well as the provision of human cells for use in drug discovery. The technology is capable of testing thousands of combinations of cell culture variables simultaneously by miniaturizing and multiplexing large numbers of stepwise cell culture experiments, increasing throughput by orders of magnitude.

Combicult is allowing us to solve many complex biological challenges associated with disease progression and, crucially, to progress our research towards direct clinical application.

Could you describe some current projects?

Our projects are divided into two main research branches. One branch focuses on developing hematopoietic cell therapies. Within this topic our lead program involves the expansion of umbilical cord blood-derived hematopoietic stem cell (UCB-HSC) for transplantation. Other hematopoietic programs include production of red blood cells and platelet-producing megakaryocytes from induced pluripotent stem cells (iPSCs). The second research branch involves drugs targeting rare cell types such as brown adipose tissue (BAT). BAT is a type of fat that is able to enhance overall metabolic activity. Larger volumes of BAT in adults is associated with lower rates of type 2 diabetes and obesity. By developing drugs derived from rare natural extracts that are able to expand and induce BAT in the body, we are producing novel therapies for these diseases as well as other metabolic disorders.

What have been your biggest successes to date?

Plasticell was able to develop a protocol – using Combicult – to increase ex vivo expansion of UCB-HSC by up to 500-fold, eliminating a major process bottleneck, and thereby allowing a single cord blood unit to potentially supply a single patient. This breakthrough has allowed Plasticell to progress our therapeutic program towards clinical application. Our successes also led to us partnering with GSK to optimize their in-house iPSC-hematopoietic cell differentiation processes. In addition, by using Combicult to create progenitors from stem cells, we have developed cell-based regenerative drug screening models for a variety of diseases, such as osteoarthritis, multiple sclerosis and Duchenne’s muscle dystrophy. To this end, Plasticell spun out a sister company, Progenitor Therapeutics, which brought considerable knowledge of cell biology and differentiation protocols to the table, while GSK provide expertise and resources in drug screening. The partnerships have been significantly aided by the co-location of Plasticell and GSK at GSK’s Stevenage Research and Development site.

What are the biggest challenges in developing and translating regenerative therapies?

Drug development is inherently risky because of the variability of biological processes. In the case of autologous cell therapies, where the patient’s own cells are reintroduced following ex vivo manipulation, behavior of cells in culture sourced from diseased donor patients may lead to significant variability – and sub-optimal performance – compared with the “gold standard” cell lines used for benchtop studies. This challenge is unusual for bioprocessing scientists and engineers, who are used to scaling up homogenous cell cultures into large bioreactor vessels. In addition, transplanted or genetically modified cells are likely to be long-lived in the patient’s body in contrast to traditional drugs that are excreted after a relatively short duration, necessitating a longer period of surveillance post-transfusion. Finally, cell-based products are likely to require more complex supply chains than traditional drugs because of their shorter shelf lives and because of the difficulty in transporting frozen cell products.

What disease areas are you working on?

We are currently working on projects suitable for a broad range of disease indications. The UCB-HSC expansion program, for example, has the potential to be applied to the treatment of over 70 different therapeutic indications, including a variety of rare hematologic diseases, such as Wiskott-Aldrich syndrome. In addition, our platelet program may be used in the treatment of thrombocytopenia (low platelet count), which commonly occurs in chemotherapy patients. Outside of the hematopoietic space, our brown adipose tissue program has the potential for developing a treatment for type 2 diabetes and obesity, as noted earlier.

What are Plasticell’s plans for the future?

Whereas Plasticell has previously focused on developing and optimizing novel protocols using Combicult, we are now confident that we are in a position to develop highly promising assets into fully-fledged therapeutic programs capable of clinical application in the very near future. In addition, we are optimistic that our technology will allow us to enter into additional collaborative programs with industrial and academic partners.

What recent external research are you closely watching?

It is a very exciting time for regenerative medicine research. The FDA approval achieved by Novartis and UPenn for their Kymriah product is likely to bring new investment and resources into developing the next generation of immunotherapy products. In addition, gene therapy – either ex vivo manipulation of autologous tissue or direct gene editing in patients – appears to be going from strength-to-strength, particularly with the promising recent clinical trial data for hemophilia B. Finally, we have been excited by the encouraging preliminary safety and efficacy data for iPSC-derived oligodendrocytes infused into spinal cord injury patients published by Asterias Therapeutics.

Where do you think the field of regenerative medicine will be in 5–10 years?

The pace of development of immunotherapy technology will likely result in the emergence of treatments for solid tumors, although they will need to be combined with other medicines for efficacy. Ideally, we also need development of ‘off-the-shelf’ allogeneic therapies to enable scaled-up bioprocessing methods, substantially reducing cost-of-goods and therefore increasing the likelihood of reimbursement and expanding the potential market. Where autologous therapy is still necessary, I foresee decentralized bioprocessing at the point-of-care, which would be a very different manufacturing paradigm. I also believe that the future holds much promise for pluripotent stem cell technology in the long-term. Despite feeling ‘nascent’ for many years, we’ve seen recent improvements in gene manipulation methods, promising safety data, and an adapting regulatory environment (particularly in Japan), all of which makes us optimistic that the technology is on its way to achieving its therapeutic potential soon.

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About the Author
Shahzad Ali

A senior scientist at Plasticell.

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