Most CRISPR companies are targeting rare genetic disorders, but Verve is breaking from the trend with gene editing therapies for coronary artery disease that could have fewer side effects, greater efficacy and better compliance than standard of care.
Verve Therapeutics Inc. launched on Tuesday with a $58.5 million series A round led by GV, licenses to foundational CRISPR IP from Harvard University and the Broad Institute of MIT and Harvard, and a pair of partnerships with Verily Life Sciences LLC and Beam Therapeutics to access delivery and gene editing technologies. Arch Venture Partners, F-Prime Capital and Biomatics Capital participated in the financing.
The company was formed around the idea that some people are born with genetic mutations that protect against heart attack, and replicating those mutations with gene editing could protect high-risk patients.
It’s pairing cardiovascular genetic research from the lab of co-founder and incoming CEO Sekar Kathiresan at Massachusetts General Hospital with a suite of gene editing technologies. Those include standard CRISPR gene editing with Cas9 and Cas12a, and Beam’s base editing technology, which involves swapping out one nucleotide for another without cutting the DNA.
Although the company hasn’t disclosed its specific targets yet, Kathiresan told BioCentury it is pursuing two sets: those that lower LDL cholesterol, and those that lower triglycerides. “We’re singularly focused on heart attack, but the different target types give us the potential to treat different patient populations by altering different lipid profiles,” he said.
Kathiresan’s lab has identified mutations in PCSK9 and ANGPTL3 and showed that gene or base editing to disrupt the targets in the livers of mice decreased plasma cholesterol and triglyceride levels. Loss of function of PCSK9 lowers LDL, whereas loss of function of ANGPT3 lowers blood triglycerides and LDL.
Verve is collaborating with Verily on its lipid nanoparticle delivery vehicles. The therapies will target genes in the liver, where most of the metabolic protein targets are produced, Kathiresan said.
Due to the uncertain regulatory requirements and safety of the new modalities, Verve plans to first treat patients with advanced cardiovascular disease before moving to earlier stage patients.
Kathiresan, who will assume the CEO role in July, said it is too early to determine a clinical timeline, but the company does plan to develop its therapies in house.
Compared with statins, lowering lipid levels with a gene editing therapy should produce fewer side effects. Compared with anti-PCSK9 antibodies, they will only need to be injected once. Four anti-PCSK9 mAbs are approved. Statins can cause muscle pain and liver damage and run the risk of drug interactions; all of these side effects reduce compliance. PCSK9 inhibitors can also cause musculoskeletal effects, such as pain, weakness and spasms, and flu-like symptoms; and the compound aren’t widely accessible.
Kathiresan said there’s no reason to believe loss of function of the target genes would produce on-target side effects because people living with the mutations are healthy.
“We know from human genetics that people who lack one copy of wild-type PCSK9 have a 40% reduction of heart attack, and those who lack two are nearly completely protected at 80-90%, and the people are healthy,” he said. “In mouse models, we see that with about 30% editing of hepatocytes, we achieve about 90% reduction in plasma PCSK9, so we may be able to get to the level of PCSK9-lowering obtained when both copies are gone in humans.”
The company’s studies include delivering the nuclease and guides to non-human primates.
Kathiresan isn’t aware of any other companies developing gene editing therapies for cardiovascular diseases. According to BioCentury’s BCIQ database, there are no other gene editing therapies in development for cardiovascular disease.
Verve Therapeutics Inc.
Technology: CRISPR-based gene editing and base editing therapies for cardiovascular disease
Disease focus: Cardiovascular
Clinical status: Preclinical
Founded: 2018 by Sekar Kathiresan, Kiran Musunuru, J. Keith Joung, Anthony Philippakis, Burt Adelman, Barry Ticho, Issi Rozen
University collaborators: Broad Institute of MIT and Harvard, Harvard University, Massachusetts General Hospital, University of Pennsylvania
Corporate partners: Beam Therapeutics, Verily Life Sciences LLC
Number of employees: 10
Funds raised: $58.5 million
Investors: GV, Arch Venture Partners, F-Prime Capital, Biomatics Capital
CEO: Sekar Kathiresan
Patents: Undisclosed number of issued patents covering gene editing and base editing technologies
Beam Therapeutics, Cambridge, Mass.
Broad Institute of MIT and Harvard, Cambridge, Mass.
Harvard University, Cambridge, Mass.
Massachusetts General Hospital, Boston, Mass.
Verily Life Sciences LLC, South San Francisco, Calif.
Verve Therapeutics Inc., Cambridge, Mass.
ANGPTL3 - Angiopoietin-like 3
Cas12a (Cpf1) - CRISPR from Prevotella and Francisella 1
Cas9 - CRISPR associated protein 9
PCSK9 - Proprotein convertase subtilisin/kexin type 9