BALTIMORE—Mammoth Biosciences co-founder and CSO Lucas Harrington spoke on the opening afternoon at the American Society of Cell and Gene Therapy (ASCGT), laying out the company’s new focus on therapeutic opportunities. 

“Last year was really when we started to go through this evolution,” he told GEN after presenting his work in an opening day session. 

“We still are a strong believer in COVID-19 diagnostics, but I think it really is about how can we make the biggest impact as fast as possible. It has been 5–6 years since these ultra-compact [CRISPR] systems were first discovered and published. It’s still surprising how little advancement other companies are making in actually pushing forward these viral-based therapies and how crowded the liver [field] continues to get. So I think it was really an assessment of where the opportunity is.” 

While Mammoth maintains some focus on diagnostics, Harrington acknowledges it is quite small. “We are always looking for folks to help us accelerate that work…. If you really want to be a diagnostics platform company, you need a massive install base. We are extremely good at the chemistry and understanding how to detect a sequence of interest. So we’re exploring opportunities to leverage partnerships to do that.” 

By contrast, in therapeutics, Harrington says, “you can’t go at it alone.” Proving that point, Mammoth recently announced its third commercial partnership, a big one with Regeneron. “Whenever we talk about the aspirations of Mammoth, we usually reference Regeneron,” Harrington says, listing reference points that include a founder-led biotech, a belief in technology, big bets, and follow the science.  

Regeneron has talked publicly about its capsid technology and being able to retarget adeno-associated viruses (AAVs) to improve tropism. Mammoth is focused on the cargo inside the AAVs, building on its research on miniature Cas nucleases. “It seemed like a pretty perfect pairing,” Harrington continued. “We think it’ll help us broaden our portfolio to accelerate how we can drive things forward.” 

Harrington won’t divulge specific indications, but says the partnership is designed more “to follow the science… we’ll find targets that we’re most excited about and test them out.” Much of what Regeneron has discussed, for example, is muscle targeting, using AAVs that are retargeted using antibodies. 

“Whether you’re a [CRISPR] company or an AAV company, you only have of what’s needed for the therapy. I think this is [a partnership] where it truly is multiplicative… We’re super excited to work with them.” 

Going small 

While there is widespread agreement that small CRISPR systems are great, “there has not been the data to support that they are robust editors” in most applications. After mining a massive set of natural diversity genomes and also conducting a large amount of protein engineering, Mammoth has “honed in on a handful of systems, one of which we highlighted for the liver programs (CasPhi).” The other is called NanoCas. “Both have features that allow us to do different things with them. We think it’s good to have both of them in the portfolio, but ultimately each program will leverage one of those two systems.” 

The application of protein engineering is usually what lifts the mini-Cas nucleases from working well in vitro to working well in in vivo models and ultimately in primates. “That is something that’s really unique about Mammoth,” says Harrington. “There are companies that focus on that diversity aspect and mining through that natural diversity. There are others that are very focused on the engineering side of things. We try and couple them together.”  

Much of the data characterizing nano-Cas comes from experiments on the APOC3 gene, using a relatively controlled environment with transient delivery in the liver. The gene has been well characterized. Another appealing aspect, Harrington says, is to start with relatively small patient segments “where we can successively derisk the technology to show that it works in a rarer indication… and sequentially expand that with the same platform.” 

The initial population of interest are patients with familial chylomicronemia syndrome (FCS). A larger group of patients has severe hyperglyceridemia, with subsets that also have acute pancreatitis. “We’re trying to reduce or eliminate the pancreatitis, which is ultimately what’s causing these patients to be hospitalized versus reduction in some lipid… This pancreatitis is happening very frequently for patients that require hospitalization.”  

“We’re trying to be pragmatic about what we can develop as a small biotech and not bite off more than we can chew,” says Harrington. But he wants to be able to move into broader indications once there is success in these smaller populations. “We’re quite happy with the efficiency and head-to-head with much larger gold-standard CRISPR systems,” Harrington saya. “These smaller systems are really going toe-to-toe with them at this point.”  

“I think we are well suited to be the first mover on this indication from a gene editing perspective,” Harrington continues. Further opportunities come in non-liver programs, packaging a variety of gene editing modalities. 

“Even with the Regeneron collaboration, that’s why we’re most excited about working with each other. Not because our systems are so small… but because we can use that other half [AAV cargo] for making a better therapy.” Examples include a fusion protein, multiple guide RNAs, or better tissue-specific regulatory elements.  

Harrington moved straight from Jennifer Doudna’s lab to creating Mammoth. “It really takes, at those early stages, the experts in the technology that care about the technology, that want to put in the years of work that it takes to get them there.” Harrington cites companies like Vertex or Alnylam as paving the way, having founders who were committed to the technology and thinking about the company on a multi-decade timescale. “That has been a proven recipe to be able to make an impact,” he said. 

Mammoth’s other two current partners are Vertex—a deal signed in 2021— and Bayer. No indications have been disclosed in the Vertex collaboration. Both partners bring a wealth of their own CRISPR expertise, which Harrington says benefits the partnerships.  

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