Leading the Movement Towards Direct Cell Conversion: An Interview With Mogrify – Technology Networks

Biotech company Mogrify is deploying its proprietary direct cellular conversion technology to develop cell therapies in a variety of disease areas, including auto-immune, musculoskeletal, respiratory diseases and in cancer immunotherapy.The platform utilizes data from next-generation sequencing and cellular networks to identify transcription factors or small molecules required to directly convert a cell, addressing key challenges that are typically associated with the safety and efficacy of cell therapies.Technology Networks recently spoke with Joe Foster, COO, Mogrify, to learn more about the platform, the challenges encountered in developing cell therapies, and to gain Mogrify's insights on the future of this exciting research space.Molly Campbell (MC): What were some of the major highlights for Mogrify in 2019?Joe Foster (JF): In the past year, Mogrify has solidified its reputation as a pioneer in the expanding field of cell therapy. Using a systematic, data-driven approach, our innovative cell conversion platform addresses many of the challenges impeding systematic discovery, process development and the manufacturing processes.At an operational level, Mogrify has seen unprecedented growth in the last year, with emphasis on world-class science. We have established a leadership team with unparalleled track records, including the appointment of Dr Darrin M. Disley OBE, as CEO and Dr Jane Osbourn OBE, as Chair. Looking forward and with plans to boost our team to 70 individuals working across all disciplines, Mogrify has also moved operations to the new Bio-Innovation Centre in Cambridge, giving our team access to state-of-the-art facilities to continue their work in developing novel approaches to cell therapy.Mogrify received MSDs Innovation Award at the 15th Annual Scrip Awards, in acknowledgement of our potential to transform future cell therapies. Dr Jane Osbourn OBE was also the first female to win the Lifetime Achievement Award, recognizing her significant contributions to the biotech industry. Mogrifys significant fundraising success was also marked at the prestigious European Lifestars Awards, which celebrates excellence in the life science industry. Here, Mogrify was recognized as the Seed Stage Finance Raise of the Year.MC: In Mogrify's opinion, what key trends can we expect to see in the cell therapy space in 2020?JF: Many of the current approaches to cell therapy involve first converting cells back into a stem cell-like stateinduced pluripotent stem cellsbefore then converting them into the cell type required.Mogrify plans to lead the movement towards direct cell conversion, or transdifferentiation, where cells can be transformed from one cell type to another, without having to go through an intermediate pluripotent stage. Direct conversion of cells would enhance the speed of cell therapy development, as cells do not need to use traditional developmental pathways to reach a mature state.

Another bottleneck in the delivery of cell therapies is that most approaches rely on autologous transplants, which are carried out using patient-derived cells. Future innovations are moving towards using allogeneic therapies, where the cells used for therapy are derived from a healthy donor. Such advances are paving the way towards the development of universal donor cells, which would turn cell therapies into off-the-shelf treatments, enhancing the scale and accessibility of the treatments.

Finally, cell therapy methods are likely to move from ex vivo approaches (where cells are isolated from the patient, reprogrammed, and delivered back into the patient), to in vivo approaches, where cell therapies are delivered directly to the recipient, for example, through the use of small molecules present in a reprogramming cocktail or direct gene editing. In vivo technologies would, therefore, be able to reprogram cells directly in living humans, expanding the scope of cell therapy in a clinical setting. Overall, future cell therapies will have the capacity to be more effective, safer, and widely accessible.

MC: What are the key challenges that currently exist when developing and testing cell therapies? How does Mogrify hope to overcome such challenges?JF: The biggest challenges in producing cell therapies surround the efficacy, safety profile, and scalability of clinical treatment regimes. To make treatments safer, delivered cells must bypass the host immune system. This can be achieved with autologous therapy, but comes at the cost of scale and efficiency, as the patients cells need to be extracted, cultured, and reprogrammed before treatment can be delivered. Genetic engineering technologies (such as CRISPR/Cas9) that can be employed to remove the antigenic potential of allogeneic cell therapies (e.g. CAR-T) can be used in conjunction with such treatments, but this brings an additional layer of complication.Another difficulty comes from the technical challenges associated with generating, culturing, and expanding the required cells. In theory, any cell type can be derived from pluripotent cells. However, determining precisely how to generate any cell from pluripotent cells is conceptually and practically complex. Each cell type would require a distinct combination of transcription factors (or small molecules) and optimized culture conditions to ensure robust conversion into the desired phenotype. These technical challenges are associated with slow progress and poor efficiency in deriving reliable therapeutic cells.

Mogrify aims to tackle these hurdles with solutions involving big data, computational predictions, and bioinformatics. Mogrifys proprietary algorithm uses next generation sequencing data to predict the combination of transcription factors necessary to reliably convert any cell type into another cell type. Mogrifys technology provides a framework for direct cell conversion, and can also identify the best culture conditions to ensure that the cell populations remain stable and viable. This greatly improves cell therapy efficiency, as mature cells are created without the often arduous and imprecise process of differentiating cells from pluripotency.

Mogrifys technology is also compatible with in vivo cell therapies, as it can identify a combination of small molecules that will drive the necessary transcriptional networks to create the cells of choice. Therefore, Mogrifys technology can also be applied to overcome safety issues associated with allogeneic ex vivo approaches, and has the potential to greatly enhance the scale at which cell therapies can be delivered.MC: Are you able to tell us more about the latest developments in Mogrify's pipeline?JF: Currently, Mogrify is focused on applying the platform to musculoskeletal disorders, cancer immunotherapy, and auto-immune, ocular and respiratory diseases. Specifically, Mogrify is committed to identifying opportunities in regenerative medicine contexts, where direct cell conversion could have strong therapeutic potential.The current lead musculoskeletal program is in the development of chondrocytes for the treatment of cartilage defects and osteoarthritis. Mogrifys platform identified a cocktail of small molecules that successfully drives the conversion of fibroblast cells to chondrocytes, which has been proven to form functional hyaline cartilage in vitro. This can even be performed using an allogeneic approach without the need for gene editing (as the cartilage is immunopriviliged). Thus, it represents an opportunity for an off-the-shelf therapy that could be a relatively inexpensive and accessible treatment. At present, this treatment is in pre-clinical stages, and has a powerful potential for success in regenerative cartilage therapy. Similarly, an in vivo method of transdifferentiating osteoarthritic chondrocytes to healthy cells is being investigated in ongoing studies using a cocktail of small molecules.

Joe Foster, COO, Mogrify was speaking to Molly Campbell, Science Writer, Technology Networks.

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Leading the Movement Towards Direct Cell Conversion: An Interview With Mogrify - Technology Networks