The Cambridge, UK based company, which was founded in 2016, said the funding will also support continued platform development and the exploration of cell reprogramming for novel therapeutic application.
Mogrify has developed a proprietary suite of technologies that utilize a systematic Big Data approach to direct cellular reprogramming and the maintenance of cell identity.
Its platforms, MOGRIFY and epiMOGRIFY, deploy next-generation sequencing, gene regulatory and epigenetic network data to enable the prediction of the transcription factors and optimal culture conditions required to produce any target human cell type from any source human cell type.
The company is deploying these platforms to develop scalable ex vivo cell therapies and in vivo reprogramming therapies for immuno-oncology, ophthalmology and other diseases with a high unmet clinical need.
We caught up with Dr Karin Schmitt, chief business officer, Mogrify at Bio Digital 2021 to hear more about how the company is leveraging this technology.
BioPharma-Reporter: Why is there a need for this systematic approach to cellular reprogramming, either ex vivo or in vivo, to develop therapies for oncology and other disease areas with high unmet clinical need?
Dr Karin Schmitt: The current crop of cell therapies is primarily derived from autologous cell sources, where donor and patient are one and the same, this minimizes the risk of immune rejection but poses potential challenges for manufacturing and patient accessibility due to limitations in the quality and viability of starting material.
As a result, developmental trends have shifted towards an allogeneic approach, seeking to replace autologous cell sources with consistent and scalable alternatives, such as induced pluripotent stem cells (iPSCs).
Since Shinya Yamanaka’s discovery of iPSCs in 2007, through the introduction of the OKSM factors, considerable emphasis has been placed on the generation of iPSC-derived cells for therapeutic use; however, progress has been limited by the requirement to recapitulate complex developmental pathways in order to produce clinically valuable cell types.
Enabled by the availability of large-scale transcriptomic and epigenetic data, systematic approaches to cellular reprogramming, such as MOGRIFY, provide a shortcut for generating cell types of interest, through the identification of the optimal combination of key regulatory factors required to drive and maintain cellular identity.
These approaches are not only capable of enhancing existing stem-cell forward reprogramming (differentiation) methods but can bypass development pathways altogether, affecting a direct cell conversion (transdifferentiation) between a mature cell type to another mature cell type.
This presents a unique opportunity to develop a new class of in vivo reprogramming therapies; through the delivery of the optimal combination of regulatory factors in vivo, it is possible to convert mature cells directly in the human body, either to replace those lost as a result of disease or return a cell with a diseased or unhealthy state to a healthy state.
BPR: Can you expand on the systematic big-data approach being employed?
KS: MOGRIFY is a direct cellular reprogramming platform which leverages transcriptomic data to identify optimal combinations of transcription factors for the conversion, via enhanced stem-cell forward reprogramming (differentiation) or direct cell conversion (transdifferentiation), of any cell type into any other cell type.
The platform first takes RNA sequencing data from the source and target cell types. The data is then processed through the MOGRIFY engine, cross-referencing transcriptomic and regulatory network data in the context of over 100 human cell types, to predict the optimal combination of transcription factors (or small molecules) for achieving directed differentiation or transdifferentiation. Based on a uniquely systematized network of influence and coverage, the platform can be repeatedly interrogated to identify factors for producing novel therapeutic cell types or finding new factor combinations for producing existing cell types whilst avoiding pre-existing intellectual property.
epiMOGRIFY is an extension of MOGRIFY that leverages epigenetic data to identify the key signaling molecules required to maintain cell identity and epigenetically support the reprogramming of cells in chemically defined media.
Acquisition of desirable cell types through cell reprogramming is likely to become an industry standard in the development of cell-based therapies; however, the need to culture those cells successfully and at scale in vitro, still represents a significant challenge. Undefined conditions can affect yield, extend production time and may be restrictive in the standardization of GMP manufacture. epiMOGRIFY provides an opportunity to closely mimic in vivo conditions by predicting optimal culture conditions to support cell maintenance, conversion and functional maturity.
The platform, leveraging the MOGRIFY network of influence and coverage engine, analyzes DNA-histone H3K4me3 methylation, a known marker of cell identity genes, to predict surface receptors with known ligands. These can then be incorporated into chemically defined culture medium as a systematic and optimizable means of supporting cell growth, survival and differentiation efficiency. This approach has been validated in Cell Systems for the culture of astrocytes and cardiomyocytes.
BPR: How do the MOGRIFY and epiMOGRIFY platforms address issues of scalability and manufacturing in ex vivo cell therapies?
KS: The technologies identify the key regulatory switches, such as an optimal combination of transcription factors or growth factors, required to control and maintain cell identity. Building on the work of Shinya Yamanaka, which relied upon educated guess and trial and error over a number of years, MOGRIFY expedites the discovery of transcription factor combinations by predicting in silico those required to directly differentiate or transdifferentiate from any starting cell type to any target cell type, such as the derivation of immune cells from iPSCs.
epiMOGRIFY extends the method through the identification of the optimal culture conditions required to maintain such cells and support reprogramming in chemically defined media, a key consideration for cGMP manufacture of cell-based therapies.
Combined, the platforms provide a unique opportunity to systematically produce any clinically valuable or even difficult-to-obtain cell type, circumventing the need for any intermediary steps or lengthy differentiation protocols and reducing the time required to produce a desired cell type. The systematic and optimizable approach reduces the need for experimental trial and error, in the context of cell reprogramming, and allows for the building of robust and reproducible processes to support the development and manufacture of scalable, cost-efficient ex vivo cell therapies.
BPR: In summary, what benefits do these platforms bring to the development of cell and gene therapies?
KS: Mogrify’s suite of proprietary technologies addresses the speed and efficiency of cell reprogramming and challenges associated with the maintenance of cell identity in the development of scalable cell therapies. These platforms, for the first time, make it possible to both systematically enhance the efficiency of stem cell-derived reprogramming and directly convert (transdifferentiate) mature cell types into other mature cell types (or states) without going through a pluripotent stem cell- or progenitor cell-state, whilst also identifying the optimal culture conditions required to maintain cells and support conversions in chemically defined media.
Mogrify is applying its proprietary and award-winning platforms to generate the scalable source of functional cell types required to transform the development of ex vivo cell therapies and pioneer a new class of in vivo reprogramming therapies for indications of high unmet clinical need in immuno-oncology, ophthalmology and other disease areas.
BPR: Can you outline the indications of high unmet clinical need in immuno-oncology, ophthalmology and other disease areas the platforms can potentially address?
KS: Mogrify is yet to disclose the specific indications against which it will be applying its cell reprogramming expertise and platform technologies; however, its internal development focus in immuno-oncology aims to address limiting factors associated with the first generation of adoptive cell therapy products. Specifically, enabling scalability whilst mitigating the risk of immune rejection and enhancing efficacy in the treatment of hematological and solid malignancies. Mogrify’s proprietary platforms are capable of underpinning future iterations of immunotherapies through systematized and robust derivation of functional immune cell types from scalable starting material. This includes the exploration of alternative cell types and subtypes with advantageous therapeutic profiles, such as improved trafficking into the tumor microenvironment, overcoming exhaustion or overall treatment efficacy.
In ophthalmology, visual impairment is most often the result of an inherited genetic trait or degeneration. Treatment is available but limited to gene therapy against RPE65 mutations and autologous retinal pigment epithelium (RPE) transplantation. In the case that the underlying mechanisms are more complex, either involving various mutations or multiple cell types, there is no treatment available. Mogrify is pioneering a new class of in vivo reprogramming therapies in ophthalmology, by introducing an optimal combination of regulatory factors in vivo, via a delivery vector, to affect an in-situ conversion of ocular cell types to address retinal degeneration.
The broad potential of both the MOGRIFY and epiMOGRIFY technologies allow continued exploration and generation of novel cell-based and in vivo reprogramming therapies for disease areas with high unmet clinical need.
BPR: Is Mogrify currently eying up new co-development partners, and can you briefly outline the work being doing with the partnerships the company has secured to date?
KS: To date, Mogrify has partnered in two key areas: 1) Co-development, leveraging its technology in combination with biopharma to produce a desired cell type, which can then be translated into a scalable and accessible cell therapy, such as Sangamo Therapeutics, for the development of allogeneic iPSC- and embryonic stem cell-derived regulatory T cells. 2) Exploratory research collaborations, such as that agreed with the MRC Laboratory of Molecular Biology developing novel protein expression systems by leveraging recent advances in direct cell reprogramming to help improve the production of proteins which are not produced sufficiently well in existing expression systems.
Mogrify has consolidated its efforts into an internal pipeline developing ex vivo cell therapies for immuno-oncology and in vivo reprogramming therapies for ophthalmology. Due to the breadth of application, in other disease areas, Mogrify will continue to develop its platforms and explore cell reprogramming for the development of novel therapeutics, seeking partners for co-development and out-licensing of exploratory assets in pulmonary, metabolic and other disease areas.
Mogrify's origins
Mogrify was founded in 2016 by Prof Julian Gough, Prof Owen Rackham and Prof Jose Polo, now based at the MRC’s Laboratory for Molecular Biology (Cambridge, UK), Duke-NUS Medical School (Singapore) and the Monash University (Melbourne, Australia), respectively.
The technology’s origins stem from Prof Gough’s work at the RIKEN Institute (Japan) and the University of Bristol, an attempt to develop a systematic approach to determine the combination of transcription factors required to drive cell identity and convert any source cell into any target cell type directly, to overcome the challenge of combinatorial explosion of possibilities.
Before this, others had experimentally determined factors that could drive a particular cell from one type to another (e.g., via transdifferentiation or via a stem cell), which took five years in the case of the Yamanaka’s OKSM discovery.
Having developed MOGRIFY, Prof Gough and Prof Rackham formed a collaboration with Prof Jose Polo to validate the predictions of the algorithm in 2014. Prof. Polo’s lab quickly validated three transdifferentiation protocols. In 2016, the platform was published in Nature Genetics, creating the foundations for Mogrify as a company.
In early 2019, Mogrify started its next growth phase, bringing on CEO, Dr Darrin Disley OBE — formerly Horizon Discovery, and Chair, Dr Jane Osbourn OBE — formerly MedImmune (AstraZeneca) and Cambridge Antibody Technology (CAT), along with a executive team, each of whom has a proven track record in the development and delivery of innovative biopharma, diagnostic and innovative research products to market.
Dr Karin Schmitt, chief business officer, Mogrify
Dr Schmitt is a globally experienced science and business executive with more than 25 years of diverse experience in biotech drug discovery, platform development and medical device companies. With a recent emphasis on cel and gene therapy, her career spans the Boston area, Silicon Valley and the Cambridge cluster. She has been an early employee in several successful start-ups, including Millennium Pharmaceuticals, Exelixis and Horizon Discovery making significant contributions to the rapid growth of these companies to IPO and beyond. She obtained her PhD in molecular biology at the University of Southern California in Los Angeles, followed by three years of post-doctoral research in genetics at the University of Cambridge.
