Beyond Yamanaka: Mogrify demystifies cellular reprogramming

Startup moves into animal studies of direct cellular reprogramming therapies for vision loss, hearing loss, and diabetes.

British cellular reprogramming outfit Mogrify recently boosted its coffers, closing a healthy $46 million Series A funding round, bringing total investment in the company to more than $50 million. The company has developed a computational platform that systematically identifies the transcriptomic and epigenetic switches required to control human cell fate.

Mogrify is using this information to enable direct in vivo reprogramming of any source cell type into any target cell type – a process known as transdifferentiation, which involves converting one cell type to another without first needing to revert them to a pluripotent, or embryonic, state. This capability is expected to have potential benefit in addressing a wide range of degenerative diseases.

Longevity.Technology: Mogrify was founded based on the groundbreaking research conducted by its scientific co-founders, professors Julian Gough, Owen Rackham and José Polo, who developed a big-data powered computational platform capable of predicting, in an unbiased manner, the reprogramming factors necessary to induce cell conversion. The company is now working on multiple programs to restore “clinically valuable” cell types, targeting conditions such as vision loss, hearing loss, and diabetes. To learn more about Mogrify’s progress, we caught up with CEO Dr Darrin M Disley.

A respected scientist, entrepreneur and investor, Disley has closely followed the cellular reprogramming field, ever since it first emerged while he was CEO of gene editing powerhouse Horizon Discovery. Professor Shinya Yamanaka’s Nobel Prize winning discovery that an adult cell could be reverted back into an embryonic stem cell capable of becoming any other cell, has sparked a global race to harness the potential of the technology to reverse disease, and potentially even aging itself.

“I was interested in cellular reprogramming because it addressed one of the major challenges, which is how to provide a consistent, pure source of a cell type, whether it’s going to be used for research, biomanufacturing, diagnostic reagents, or clinical therapeutic applications,” he says. “What Yamanaka showed for the first time is that if you identified the right points of intervention within the cellular transcriptome, and you painstakingly studied 24 transcription factors, and got a bit lucky as well, then you could reprogram skin fibroblasts into inducible pluripotent stem cells.”

Building on Yamanaka

Despite the huge significance of Yamanaka’s work, which demonstrated that evolutionary pathways could be countered, and the course of cell fate could be changed, Disley knew that much more work was needed before any real human benefit could be realized.

“It took Yamanaka’s group seven years, and they studied 24 transcription factors,” he explains. “There are 1,700 transcription factors acting on up to 25,000 different genes, and then there’s the extracellular context, the disease microenvironment, epigenetics, and so on. So, that approach, while showing us the way, was never going to be able to be applied systematically.”

When Disley first came across the work being conducted in academia by Mogrify’s co-founders, he knew they were onto something big.

“They were working on building the bioinformatics needed to effectively take a de novo cell type and make predictions of the transcription factors that would drive the cell fate from state A to state B,” he says. “They did a retrospective analysis of all the conversions that have been done before, and then they did a whole load of de novo conversions that had never been done before in the literature. And it panned out extremely well.”

Under the hood

This research is what led to the seminal paper in 2016, which graced the front page of Nature Genetics, and was, essentially, the very system on which Mogrify is built.

Beyond Yamanaka: Mogrify demystifies cellular reprogramming
UK-based Mogrify is headquartered at the Cambridge Science Park.

“What our platform does is enable you to identify the key cell switches, the combinations of transcription factors that are highly regulatory over the driving of cell fate,” says Disley. “With our system, you’re able to get a ranking of each of the 1,700 transcription factors individually and its effect on all 25,000 genes, and all the downstream cascades of DNA-protein and protein-protein interactions, so you can then find the optimum combination that will give you the result you want.”

By having a quantitative measure of the impact of every transcription factor, Mogrify’s platform provides the ability to look qualitatively at which combinations of factors deliver the specific cellular reprogramming effects required. Disley gives the example of replacing cochlear hair cells, the loss of which is a major factor in hearing loss.

“The thing is, there are different types of cochlear hair cells, and not all of them are linked to hearing, so the field is littered with failures,” he says. “With our platform, because you’ve got all possible combinations, you’re not just picking the one that you’ve studied empirically in the lab or have 20 years of expertise in. It enables you to look at the potency of each transcription factor and then combine them to find what gives you the maximum regulatory network coverage while also targeting the right genes that will lead to mature functional cells.”

Cellular reprogramming goes direct

What Mogrify is doing, explains Disley, is systematizing the Yamanaka approach for all cell types.

“Whether you want to go from a somatic cell to a somatic cell, or you want to work with stem cells in a cell therapy approach, we can do it,” he says. “In our own therapeutic programs, we’re doing transdifferentiation – targeting cells that already exist in your body and converting them into other adult cells without following stem cell or evolutionary biological approaches.”

Beyond Yamanaka: Mogrify demystifies cellular reprogramming
Studying direct cellular reprogramming in the Mogrify lab.

The direct transdifferentiation approach was deemed by Mogrify to be the best application of the technology from a therapeutic perspective.

“We’re focused on in vivo reprogramming as a therapeutic modality – we decided to deprioritize the ex vivo cell therapy application, which is crowded and has significant downstream process challenges,” says Disley. “Our pipeline is based on certain types of degenerative diseases, and the ones we’ve picked are very specific to what can be solved now with the state of the art.”

The diseases that Mogrify is going after are particularly relevant in the context of our rapidly aging society.

“The main reason that I got involved with this was because I felt that for the first time, you might be able to have a real impact on common chronic degenerative diseases of aging,” says Disley. “I’m talking about things like blindness and deafness, for which there’s almost no effective treatments. And then you’ve got the metabolic diseases like diabetes – there are approaches that are systemically treating the symptom, but they’re not actually bringing beta cells back so that they can function normally. So, I was really interested in having a serious impact on these kinds of diseases.”

The road to the clinic

For Mogrify, delivery of the reprogramming therapy was a key consideration when it came to making decisions on its target indications.

“Once you’ve identified the combination of factors that will drive the cell conversion efficiently, you’ve got to deliver those transcription factors into the cell, and that will be a very specific cell, so you need a tissue-specific promoter for that cell,” says Disley. “You need to be able to deliver, for example, three or four transcription factors to the cell, so having a precedented local delivery approach is fundamental, which is why we’re targeting indications and cells where we high level of confidence in using a localized delivery approach.”

Having demonstrated good success in cells and tissues in the lab, Mogrify is now ready to move into preclinical studies in animal models.

“We wanted to have a very high level of confidence before we went into animal studies, that we both got a conversion, the cells are functional, and that there is strong molecular evidence of conversion mechanism,” says Disley. “We believe we now have a high bar of evidence ex vivo so we’re ready to go into animal studies now, where we’ll be doing similar experiments in vivo.”

The company is now fully focused on demonstrating an in vivo proof of mechanism and proof of concept in at least one of the diseases it is targeting. 

“This would be supported by the comprehensive ex vivo data we’ve already generated in primary human tissues, explants, organoids and so on,” says Disley. “If we can achieve that, we should be able to raise a really good Series B to take the programs through into the clinic and through Phase 1 trials.”

If all goes to plan, Disley expects Mogrify should be ready to move at least one of its programs into the IND-enabling phase in around 18 months’ time.

Photographs courtesy of Mogrify