Therapeutics


Mogrify technology outline: (A) differenrential expression; (B) scoring transcription factors


using regulatory network; (C) matching of differential expression to optimal transcription factor combination


patients in trials but still causes a notable immune reaction with common adverse effects including sinusitis (sinus inflammation) and nasopharyngitis (inflammation of the upper throat and upper res- piratory tract). Additionally, in the cartilage (affected by defects and osteoarthritis) and the back of the eye, where little vasculature is found, the hosts immune cells do not come in contact with the implanted cells. This has led to several trials using unmodified chondrocytes and retinal pigment cells to treat cartilage defects and age- related macular degeneration respectively, some of which have shown good success but are not com- mercially viable as a result of the second major hurdle: manufacturability. Even if an allogeneic therapy is possible – either


by gene editing the cells or by the immunopriv- iliged nature of the host tissue – the cells need to be manufactured at scale in order to provide sufficient material for all patients that require an off-the- shelf product. Scientifically, this manufacturing hurdle is two pronged. Firstly, we need to discover the ability to make cells and, secondly, we need the ability to culture those cells. Unfortunately, many differentiated cells in the body do not have the innate ability to divide. Chondrocytes, for exam- ple, create an extracellular matrix which makes up the cartilage but directly inhibits their growth, and terminally differentiated neurons do not divide because they lack centrioles. Yamanaka’s discovery of the OKSM factors to make iPSCs was thought to open up the possibly of producing any cell type by following the developmental pathways (described by Waddington as small balls rolling down a hilly landscape). Following the expansion of iPSCs this would allow the production of large quantities of any cell. However, to do so the dis-


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covery of the combination of factors required to convert iPSCs into a specific cell type remains to be discovered, for which the number of combinations are astronomical (~1062).Moreover, even if a com- bination is discovered, identifying suitable culture conditions for the cells to be maintained in their transcriptomic state remains a huge challenge. Many cells are known to be very hard to culture such as megakaryocytes, zombie and foam cells, all of which have therapeutic potential which remains to be unlocked. This hurdle of cell conversion is being


approached in many ways. OxStem, an Oxford University spin-out, carries out phenotypic screen- ing using small molecules to create the desired cell type in vivo. The Cambridge-based company Mogrify has leveraged large amounts of transcrip- tomic (FANTOM5) and regulatory data (MARA& STRING) to develop a systematic algorithm which predicts the combination of transcription factors required to convert any human cell type into any other human cell type without going through a pluripotent stem cell state (ie transdifferentiation). This technology represents the first systematic con- trol of the transcriptomic network and therefore is to transcriptomics what gene editing technologies such as ZFNs/CRISPRs are to genomics. The tech- nology has been validated inmore than a dozen cell types in quick succession, which shows great promise for the future of scalable cell manufactura- bility. Similarly, this technology can be extended to identify the culture conditions systematically by sta- bilising the cell type in its epigenetic state by sus- taining the transcriptomic state. Looking further into the future, such technolo-


gies have the potential to create the next generation of cell therapies. Instead of autologous or allogeneic


Drug DiscoveryWorld Summer 2019


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