Sekar Kathiresan showcases historic monkey data in hunt for a once-and-done gene editing approach to prevent heart attacks

In a first for CRISPR — a field that’s seen quite a few historic moves in the past couple of years — scientists have slashed cholesterol and lipid levels in monkeys using a technique known as base editing, generating crucial proof-of-concept for both the biotech behind the experiment and a key partner.

Verve Therapeutics designed two similar experiments to test whether they can reproduce protective mutations in a pair of genes using an adenine base editor, which precisely alters a chosen A to a G in the genome. CEO and co-founder Sekar Kathiresan presented the results at a virtual keynote for the International Society for Stem Cell Research over the weekend.

The base editors appeared to have essentially turned off genes, shutting down production of corresponding proteins. That translated to a 60% drop in LDL with the PCSK9 therapy and a 64% plunge in triglycerides on the ANGPTL3 treatment.

When it comes to lowering the colloquial bad cholesterol, “60% is on par if not better than any other treatment out there,” Kathiresan told Endpoints News just after his presentation.

These results are the culmination of Kathiseran’s decades-long search for genetic clues for solving coronary heart disease, the leading cause of death in the world. While director of the Center for Genomic Medicine at Massachusetts General Hospital and the Cardiovascular Disease Initiative at the Broad Institute, he and colleagues had identified eight genes that harbor rare mutations associated with resistance to myocardial infarction. After showing in mice that they could administer a one-time treatment for permanent lowering of cholesterol, he left academia to work on bringing it to humans full-time.

There is, of course, still a long way to go. But Kathiresan believes the new data have lit up Verve’s path to the clinic.

They are still choosing between the PCSK9 and ANGPTL3 programs as their lead candidate. Once they do — the deadline will be the end of the year — an IND for patients genetically predisposed to high risk of heart attack is in sight for 2022.

Both programs demonstrated dramatic reductions in the target protein, cutting 89% of PCSK9 and 95% of ANGPTL3 from the bloodstream. With the study limited to two weeks, though, the durability questions loomed large during the Q&A.

“We have encouraging data out to several months now,” Kathiresan said, expressing confidence that the editing will be stable long-term.

The rate of DNA reached 67% of the liver for PCSK9 and 60% for ANGPTL3 which, Kathiseran pointed out, represents the majority of hepatocytes as around 30% of the liver is supporting tissue. Getting to not just mature hepatocytes but also stem cells would be crucial. In previous research by other groups, scientists have observed continued editing in mice cells even when they chop out parts of the liver and let it regenerate.

Considering the base editors were deployed in vivo, safety was also paramount. Verve reported no off-target edits in the 108 sites measured — owing, Kathiresan said, to the technology they have licensed from Beam Therapeutics.

Unlike the first generation of CRISPR editing, base editing doesn’t snip at the site Cas9 brings it to; rather, through an enzyme, it converts one base to another chemically.

“So it’s kind of ingenious because it uses the GPS localization feature of Cas9, but it doesn’t use the double-strand break feature of Cas9,” he said.

Apart from the mRNA that forms the editor, every Verve therapy also consists of a guide RNA — picked out from hundreds — directing the machinery to the desired spot, all encapsulated in a lipid nanoparticle engineered in collaboration with Vancouver-based Acuitas.

Delivering with lipid nanoparticles instead of a viral vector is a deliberate choice.

“We need to get in, get the editor and the guide RNA, get the editing to happen and then everything to go away as quickly as possible,” Kathiresan said, “because the longer the liver is exposed to the editing machinery, the more likely you are to get off-target effects. and lipid nanoparticles allow delivery and then resolution of the process within a couple of days.”

Also deliberate is their decision to partner widely and assemble — not invent — all the tools that might aid their work. Base editors aren’t going to cover the full spectrum of possible and necessary changes as Kathiresan and his team go down their prioritized list of eight genes. But they are taking it one step at a time.