When a researchers talk about gene editing, they’re usually thinking about several steps. First you need to zero in on the defective gene; then, depending on the need, you’d want to knock out, replace or insert genetic material.
CRISPR/Cas9 technologies have transformed the field by making a breakthrough for the first problem. Inducing double-stranded DNA breaks, or achieving single-letter changes as base editing allows, have promising applications in multiple diseases that are starting to get tested in humans.
But Versant Ventures, one of the pioneering investors in the space, still sees a gap. And they’re teaming up with a group of prominent Stanford researchers — plus a seasoned biotech exec — to fill it.
“Achieving high-efficiency targeted gene integration has been a critical objective of gene editing for more than 15 years, but only now is this technologically possible,” Jerel Davis, Versant’s Vancouver-based managing director, said.
Graphite Bio has $45 million to start things off, but the money matters little when compared to the rich brain bank it’s drawing from.
Matthew Porteus, an academic founder of CRISPR Therapeutics, is lending the tech platform to create this next-gen play alongside gene therapy expert Maria Grazia Roncarolo.
Drawing from research work led by Danny Dever while a postdoc at Porteus’ lab, Graphite’s big promise is to increase integration efficiency from less than 1% to greater than 50% “across diverse genetic lesions in a wide range of cell types.”
Specifically, Dever and Porteus showed that they could correct the sickle β globin gene in patient-derived hematopoietic stem cells ex vivo by combining Cas9 ribonucleoproteins with a donor molecule that serves as a template, delivered in recombinant adeno-associated viral vectors of serotype 6 (rAAV6).
That could make for a much more scalable replacement for transplants, they wrote in a 2017 paper describing mouse studies.
“Notably, we devise an enrichment paradigm to purify a population of HSPCs with >90% targeted integration,” they wrote. “We also show efficient correction of the SCD-causing E6V mutation in patient-derived HSPCs that after differentiation into erythrocytes, express adult β-globin (HbA) mRNA, confirming intact transcriptional regulation of edited HBB alleles.”
Chief executive Josh Lehrer is leading the charge to start Phase I for this program in early 2021, bringing all the sickle cell knowledge and experience from a six-year run as Global Blood Therapeutics, most recently as CMO. More preclinical therapies are in the works for unnamed serious diseases. Samsara BioCapital is joining Versant for the launch round and sending Abe Bassan to the board, which also features Davis and Carlo Rizzuto from Versant.