Vertex Pharmaceuticals was already an enthusiastic backer of very early gene editing projects, with deals in place with the likes of Crispr Therapeutics and Arbor Biotechnologies. The group spread its bets even further today, signing up another Crispr player, Mammoth Biosciences, for $41m up front.
The agreement involves in vivo gene editing but other details are thin on the ground – the companies will not even say which diseases they are looking at. Still, Mammoth’s co-founder and chief scientific officer, Lucas Harrington, tells Evaluate Vantage that, in general, the group is focused on potential one-time cures rather than redoseable therapies, which could give some clues.
The smaller the better?
Privately-held Mammoth’s unique selling point is that it has created “ultra-small” Crispr systems based around enzymes such as Cas14 and Casɸ, both of which the group licensed from the lab of another co-founder, the Crispr pioneer Jennifer Doudna.
By contrast, the large size of SpCas9, the most widely used Crispr enzyme, can make it tricky to package up for delivery alongside a guide RNA. This is particularly relevant for AAV viral vectors, which have a limit on the size of the cargo they can carry.
“SpCas9 is about 1,370 amino acids. Some of the systems we’ve discovered are less than 500 – some of them around 400,” says Mr Harrington. “You don’t have the same payload restrictions as with SpCas9.”
Of course, there are other ways to deliver gene editing machinery and, as well as viral vectors, Mammoth is working on non-viral methods such as lipid nanoparticles (LNPs).
Although LNPs do not have the same size restrictions as AAVs, there are still advantages to using small cargoes with the former, for example durability and consistency, according to Mr Harrington. “Also, if your cargo is a quarter or a third of the size, you can now fit three times the number of molecules in there, so you can get dosing efficiencies as well.”
Mammoth and Vertex are not saying which delivery method or methods the partnership covers.
Another advantage Mammoth claims is the high accuracy of its systems, which could minimise off-target effects, although Mr Harrington will not give more details about how the company has achieved this.
Neither will he say when the Vertex-partnered projects might go into the clinic.
On intellectual property, however, he is more forthcoming. Mr Harrington believes that Mammoth can sidestep the legal battle that has ensnared the original Crispr/Cas9 players. “We’ve worked very hard on making sure our systems are much cleaner in terms of IP than the original Cas9.”
There is clearly excitement around Mammoth: the group raised a $150m series D in September, giving it unicorn status. And today’s deal with Vertex provides further validation.
But the group now has to make sure it doesn’t get lost among Vertex’s growing roster of gene editing partners. On this point, Mr Harrington says: “There are a lot of diseases out there, and it’s not one size fits all. Many diseases require specialised Crispr systems, and that’s what Mammoth brings.”
|Vertex’s advanced therapy collaborations|
|Mammoth Biosciences||Ultra-small Crispr systems for in vivo gene editing||Two undisclosed rare diseases||$41m up front, $650m milestones||Oct 2021|
|Arbor Biotechnologies||Crispr-edited ex vivo cell therapies||T1DM, SCD & beta-thal||Up to $1.2bn||Aug 2021|
|Gene editing||CF & “four other diseases”||Not disclosed||Jan 2019|
|Crispr Therapeutics||Crispr/Cas9-edited ex vivo cell therapy (CTX001)||SCD & beta-thal||$900m up front, $200m milestones||Apr 2021|
|Crispr/Cas9-based therapies||DMD & DM1||$175m up front||Jun 2019|
|Crispr/Cas9-edited ex vivo cell therapy (CTX001)||SCD & beta-thal||Any new terms undisclosed||Dec 2017|
|Crispr/Cas9-based therapies||CF, SCD & other diseases||$105m up front, $420m milestones on any project licensed in||Oct 2015|
|Moderna||Gene editing via mRNA||CF||$75m up front, $380m milestones||Sep 2020|
|mRNA therapeutics||CF||$40m up front, $275m milestones||Jul 2016|
|Affinia Therapeutics||AAV vectors for gene therapy||DMD, DM1 & CF||Up to $1.6bn||Apr 2020|
|CF=cystic fibrosis; DM1=myotonic dystrophy type 1; DMD: Duchenne muscular dystrophy; SCD=sickle cell disease; T1DM=type 1 diabetes. Source: Evaluate Pharma & company releases.|
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