Moonwalk Biosciences launched earlier this year, crashing the epigenome editing bash. So it is not surprising that the company’s name is not inspired by Neil Armstrong and Buzz Aldrin’s adventures on the moon but rather by a 1980s dance move popularized and associated with Michael Jackson—who did not invent the gliding backslide.
“The relation to science is that when you think about the epigenome, we think about changes over time and with disease,” said Alex Aravanis, MD, PhD, CEO and co-founder of Moonwalk Biosciences. “The epigenome of a healthier, younger cell often tells us how we want to modify it. The concept of the dance is that sometimes to move forward, you have to move backward. That’s the analogy to the epigenome—that you actually have to go back in time towards a genome that’s in a healthier and younger state.”
At this year’s ASGCT, Aravanis said that the team at Moonwalk is excited to show how they intend to do that dance behind data for their two major platform components: the EpiRead and EpiWrite technologies.
Learning to read…
To say Aravanis has a bit of experience “reading” genomes is an understatement. Previously, as Illumina’s chief technology officer, SVP, and head of research and product development, Aravanis led the launch of the next-generation sequencing industry’s leading products for genomics-based research, and clinical applications, including whole genome sequencing, comprehensive genomic profiling of cancer, COVID-Seq, and the most advanced AI tools for interpreting genomic information.
So, when Aravanis says that Moonwalk will be showing data on T cell epigenetic maps and particular methylation maps that he believes are the “first complete methylation maps of the major T cell subsets,” there’s a good chance there’s something to the claim.
“I think a big differentiator for Moonwalk is that we have extraordinary capabilities around the human methylome, interpreting it and predicting which sites to modify, both for known targets and discovering new targets,” said Aravanis. “We are really opening up the methylome now to see it and all of its details, and then looking at it in terms of targets for modifying these cells—what is driving the biology and where we can go in and intervene to change the phenotype.”
According to Aravanis, there was no single-cell methylome data until now, and the vast majority of CpG sites had yet to be characterized. Moonwalk has specifically developed an assay for single-cell methylome characterization at the genome level. Aravanis claims that for the first time, they can assay all 28 million CpG sites coherently.
“Maybe someone had taken an array—and I developed most of the modern versions of those—those are often only a percent or two of the methylome,” said Aravanis. “Maybe it’s a few hundred thousand or a million, but again, a very small percentage of the total methylation sites. In totality, probably >95% of the [EpiRead] data is totally novel just because it hasn’t been done in the subset. It’s never been done in the vast majority of sites across the human methylone, and it certainly hasn’t been done at single cell resolution.”
…and to write
Moonwalk will also show how their epigenetic editing technology, EpiWrite, works when seven simultaneous multiplexed epigenome edits are applied to primary human cells, resulting in over 85 percent of cells having all seven edits, a breakthrough in epigenetic engineering.
Aravanis said that Moonwalk has received a lot of interest from various pharmaceutical companies because it provides solutions to biochemical pathways involving multiple genes. For example, while there are individual targets where you can get large effect sizes, there are pathways where multiplexed epigenome editing could be useful to tamp down the activity of multiple genes. Aravanis argues that with more traditional CRISPR approaches, like nucleases or base editing, there are serious concerns when multiplexing around just the cumulative damage you’re doing—the so-called genome toxicity.
“Every time you cut or nick DNA, you introduce insertions, deletions, and translocations,” said Aravanis. “Even the more gentle versions of it still do damage, and that just compiles as you do more and more of it. Whereas, because we’re not fundamentally damaging the DNA, it appears we have a much higher capacity to multiplex. We’re actually pushing out towards double digits, and we think we’ll get there. That opens up the ability to make a lot of modifications in one go since we’re not cutting or nicking the DNA.”
This is particularly useful when thinking about medicines like complex T cell therapies, where three or four genes are being modified. Aravanis said that traditional CRISPR nuclease methods would be very hard to use in a manufacturing setting to make therapies like CAR T cells because they need to be edited and expanded over and over again, which can cause genotoxic damage.
“The data we haven’t shared yet does demonstrate the durability and heritability of these modifications,” said Aravanis, who conceded that they aren’t the only ones to show that. Indeed, there’s enough data from private companies like Tune Therapeutics and academics that shows that when you make these modifications to the methylome, they endure, meaning that the cell does not reverse them when they undergo mitosis.
Beyond DNA methylation
While DNA methylation is a key component that Moonwalk is attempting to understand and manipulate, Aravanis stated that the company is developing technologies for other epigenomic modifications, such as histones. This is especially important when attempting to activate endogenous genes that may have tissue-specific expression or are suppressed by age or disease. There are not many good tools in the pharmacology toolbox or gene editing for activating an endogenous gene in a way that is long-lasting and safe, which is where Aravanis believes epigenome engineering holds a lot of promise because there are numerous ways genes are epigenetically regulated.
“We have been able to activate genes and we think that’s a really promising capability,” said Aravanis. “Some of the therapeutic targets we were looking at require gene activation. There’s actually some really great known biology and disease pathways, but nobody has tried to drug them per se because they require gene activation, whereas in general people look for things where you can inhibit something or break something.”
Aravanis didn’t provide any information or updates on any drug programs, saying that they don’t have anything to share yet but hope to be doing so later in the year or early 2025.
