First In Vivo Base Editing Therapy

Calendar July 14, 2022 | Posted by admin

Verve Therapeutics has dosed its first patient with what it said today was the first in vivo base editing therapy to reach the clinic, a potential treatment for Heterozygous Familial Hypercholesterolemia (HeFH). Base editing is a genome-editing method related to the CRISPR–Cas9 system.

Verve, which specializes in gene editing therapies for cardiovascular disease, said that its VERVE-101 is a single-course gene editing treatment designed to reduce the low-density lipoprotein cholesterol (LDL-C) that drives HeFH. VERVE-101 consists of an adenine base editor messenger RNA that Verve has licensed from another base editing therapy developer, Beam Therapeutics, as well as an optimized guide RNA targeting the PCSK9 gene packaged in an engineered lipid nanoparticle.

By making a single A-to-G change in the DNA genetic sequence of PCSK9, VERVE-101 aims to inactivate that target gene. Verve reasons that inactivation of the PCSK9 gene has previously been shown to up-regulate LDLR expression, leading to lower LDL-C levels and thus reducing the risk for atherosclerotic cardiovascular disease (ASCVD)—of which HeFH is a subtype. Base editing is a pinpoint method for engineering base substitutions without cleaving the DNA double helix backbone. The underlying technology was developed in the lab of Harvard University chemist David Liu, PhD—who co-founded Beam with Feng Zhang, PhD, and Keith Joung, MD—with research led by two postdocs, Alexis Komor, PhD, and Nicole Gaudelli, PhD.
Beam is also expected to enroll its first patient later this year in its first clinical trial for one of its base editing therapies, BEAM-101 for the treatment of sickle cell disease (SCD). Beam also plans two IND applications this year—one for its second SCD candidate BEAM-102, and the other for BEAM-201, a treatment for relapsed/refractory T cell acute lymphoblastic leukemia/T cell lymphoblastic lymphoma.

“The dosing of the first human with such an investigational base editing medicine represents a significant achievement by our team and for the field of gene editing,” Sekar Kathiresan, MD, Verve’s co-founder and CEO, said in a statement. “Preclinical data suggest that VERVE-101 has the potential to offer people with HeFH a game-changing treatment option, transforming the traditional chronic care model to a single-course, life-long treatment solution,” Kathiresan added.

Andrew Bellinger, MD, PhD, Verve’s chief scientific and medical officer, added that VERVE-101 is intended to improve upon current standard of care treatment for HeFH. He stated that less than 20% of patients achieve LDL-C goal levels due to the limitations of the chronic model, which include requirements for rigorous patient adherence, regular health care access, and extensive health care infrastructure.

Source: https://www.vervetx.com/
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How To Substantially Lower LDL Cholesterol Levels

Calendar July 6, 2020 | Posted by admin

Verve Therapeutics, a next-generation cardiovascular company, today announced the presentation of new preclinical proof-of-concept data in non-human primates that demonstrate the successful use of base editing to turn off a gene in the liver and thereby lower blood levels of either LDL cholesterol or triglyceride-rich lipoproteins, two factors leading to coronary atherosclerosis. Verve is developing one-time gene editing medicines that safely edit the adult human genome and mimic naturally-occurring cardioprotective variants to permanently knock out cholesterol-raising genes in the liver and treat coronary heart disease. The data were presented at the International Society for Stem Cell Research (ISSCR) 2020 Virtual Annual Meeting.

In a keynote address titled, “From reading the genome for risk to rewriting it for health,” Sekar Kathiresan, M.D., co-founder and chief executive officer of Verve Therapeutics, presented the results of recent studies utilizing adenine base editing (ABE) technology, licensed from Beam Therapeutics, in which substantial lowering of plasma LDL cholesterol or triglycerides was successfully demonstrated in non-human primates. Base editing is a gene editing technology developed to enable precise and permanent rewriting of a single DNA letter in the genome.

“At Verve, our goal is to develop medicines, given once in life, that precisely edit targeted genes in the liver to permanently reduce LDL cholesterol and triglyceride levels in adults with coronary heart disease, the leading cause of death in the U.S. and worldwide,” said Dr. Kathiresan. “These proof-of-concept data, which to the best of our knowledge represent the first successful application of the base editing technology in non-human primates, show that we can safely edit the primate genome at highly efficacious levels to significantly lower blood LDL cholesterol and triglycerides. The findings are very encouraging and add to our growing body of evidence in using both base editing and CRISPR-Cas9 in vivo against various gene targets. We expect to choose a lead program by year-end 2020 with the goal of initiating human clinical studies within the next three years.”

The studies were conducted in a total of 14 non-human primates and evaluated in vivo liver base editing to turn off proprotein convertase subtilisin/kexin type 9 (PCSK9), a gene whose protein product elevates blood LDL cholesterol or angiopoietin-like protein 3 (ANGPTL3), a gene whose protein product elevates blood triglyceride-rich lipoproteins. Verve’s proprietary drug product consisting of the ABE mRNA and an optimized guide RNA packaged in an engineered lipid nanoparticle was delivered through a single intravenous infusion. Across two separate studies, seven animals were treated with the drug product targeting the PCSK9 gene and seven additional animals with the drug product targeting the ANGPTL3 gene.

Whole liver editing, blood protein and lipid levels were measured at two weeks and compared to baseline. The program targeting PCSK9 showed an average of 67% whole liver PCSK9 editing, which translated into an 89% reduction in plasma PCSK9 protein and resulted in a 59% reduction in blood LDL cholesterol levels. The program targeting ANGPTL3 showed an average of 60% whole liver ANGPTL3 editing, which translated into a 95% reduction in plasma ANGPTL3 protein and resulted in a 64% reduction in blood triglyceride levels and 19% reduction in LDL cholesterol levels.

Source: https://www.vervetx.com/

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