MOGRIFY® PLATFORM

Systematically predict the transcriptomic switches required
to produce any target cell type from any source cell type.

The MOGRIFY® technology was developed as a systematic means of identifying the key regulatory switches, such as an optimal combination of transcription factors, required to drive cell identity. The platform can be used to enhance existing stem-cell forward reprogramming methods or can bypass development pathways altogether, affecting a direct transdifferentiation between a mature cell type to another mature cell type.

The figure below shows the step-wise scientific approach used in order to achieve such predictions. Firstly, the gene expression levels are compared in the source and target cell types (consisting of FANTOM5 and other proprietary data). This step determines the changes in the gene expression levels that are needed in order to achieve the conversion. Secondly, transcription factors are scored compared to the required changes in gene expression levels by both direct and indirect influences (using the MARA and STRING databases). This includes the regulatory network information on protein-DNA interactions as well as protein-protein interactions. Thirdly, local transcriptomic regulatory networks are built to calculate the effect of the transcription factors on gene expression levels. Lastly, the optimal combination of transcription factors is predicted to maximize network coverage, while avoiding redundancies, to achieve the necessary changes in gene expression for the cell conversion to occur.

In addition to identifying transcription factor-driven cell conversions, small molecules that are known to affect the expression of the key predicted transcription factors can be identified from published literature to create a small molecule conversion cocktail. This has the added benefit of not requiring the transduction of the transcription factors and consequently holds greater potential as an in vivo reprogramming therapy.

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Mogrify Direct Cellular Conversion Technology

Step 1 Calculation of contextual gene expression

Mogrify Direct Cellular Conversion Technology

Step 2 Identification and scoring of genes that require change from source to target cell

Mogrify Direct Cellular Conversion Technology

Step 3 Building local regulatory network of influence around each transcription factor (TF)

Mogrify Direct Cellular Conversion Technology

Step 4 Scoring of the conversion potential of each TF and optimization of network coverage with combinations of TFs

Over 150 cell types, of which 32 cell conversions (13 successfully validated in vitro) are covered in the foundational patent. Images adapted from Rackham OJL et al. A predictive computational framework for direct reprogramming between human cell types. Nature Genetics (2016).

EpiMOGRIFY PLATFORM

Systematically predict the epigenetic switches required
to drive and maintain cell identity.

EpiMOGRIFY is an extension of the Company’s proprietary direct cellular conversion technology, MOGRIFY®, that enables the identification of the optimal culture conditions required to maintain cells and support conversions in chemically defined media. This can be applied in cGMP manufacture and enhances directed differentiation or cell conversion to support the development of scalable off-the-shelf therapies for diseases with a high unmet clinical need.

EpiMOGRIFY combines gene-regulatory information with a model of a cell’s epigenetic landscape and leverages changes in the level of DNA-histone methylation (H3K4me3 modifications). The platform utilizes data from more than 100 human cell/tissue types (available via the ENCODE and Epigenome Roadmap consortia) to accurately define culture conditions that can maintain the cell identity or induce cell conversion.

The predictive power of EpiMOGRIFY has been validated in two ways: cell maintenance and differentiation. EpiMOGRIFY-predicted factors are able to maintain astrocytes and cardiomyocytes in vitro in chemically defined media, and promote the generation of astrocytes and cardiomyocytes from neural progenitors and embryonic stem cells, respectively. In both cell maintenance and differentiation, EpiMOGRIFY defined conditions performed as well or better in all cases when compared to existing undefined conditions, significantly increasing cell growth and survival, as well as resulting in a higher differentiation efficiency.

EpiMogrify ONE

Step 1 H3K4me3 histone modification sequencing using ChIP-seq (chromatin-immunoprecipitation)

EPIMOGRIFY 02

Step 2 Cell identity gene identification using ChIP-seq data (ENCODE)

EPIMOGRIFY 03

Step 3 Key receptor identification, using the same “engine” as MOGRIFY® (considers both direct and indirect effects)

EPIMOGRIFY 04

Step 4 Ligand identification for both paracrine & autocrine ligands

Patent pending on the EpiMOGRIFY platform, validated conversion and maintenance of specific cell types. Images adapted from Kamaraj et al., EpiMogrify Models H3K4me3 Data to Identify Signaling Molecules that Improve Cell Fate Control and Maintenance. Cell Systems (2020).

Applying Mogrify and EpiMogrify

To ENHANCE

Efficacy

  • Enhances existing stem-cell forward reprogramming methods.
  • Bypasses development pathways altogether, affecting direct transdifferentiation between a mature cell type to another.

Safety

  • Produces mature cells to avoid the tumorigenicity- and immunogenicity-associated characteristics of pluripotent stem cells.
  • Queries FANTOM5 and other proprietary data sources to improve prediction quality, prediction accuracy and cell conversion efficacy.

Scalability

  • Produces any target cell type from any source cell type.
  • Identifies the optimal culture conditions required to maintain and support the conversion of cells in chemically defined media.
  • Capacity to identify small molecules known to affect the expression of the key Mogrify predicted transcription factors, avoiding the need for their transduction, and offering greater potential as an in vivo reprogramming therapy.

Our

PIPELINE

AREA Sample Acquisition Bioinformatics In vitro PoC In vivo PoC IND Clinical Marketing
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