Verve Therapeutics announced new in vivo data from the company’s proprietary lipid nanoparticle (LNP) delivery technology leveraging an internally discovered GalNAc-targeting ligand for delivery of base editors to the liver. Findings highlight the ability of Verve’s novel GalNAc-LNP to achieve high efficiency liver delivery and base editing in mouse models of homozygous familial hypercholesterolemia (HoFH), a form of atherosclerotic cardiovascular disease (ASCVD). Verve is advancing a pipeline of single-course in vivo gene editing programs for the treatment of ASCVD indications, including HoFH. Verve’s gene editing programs consist of LNPs that encapsulate mRNA encoding for a gene or base editor, as well as a guide RNA targeting the gene of interest expressed in the liver. For patients with HoFH, LNP-mediated liver delivery is challenging because complete deficiency in the low-density lipoprotein receptor (LDLR) gene in this patient population often drives HoFH pathophysiology, and uptake of LNPs into the liver is generally thought to be through a LDLR-dependent pathway. To overcome this, Verve has developed a novel approach that bypasses the LDLR and delivers LNPs to the liver through a different receptor. Asialoglycoprotein receptors (ASGPRs) are highly expressed in the liver with a high capacity to mediate uptake into the liver, independent of LDLR. As such, by incorporating an internally discovered GalNAc molecule, the targeting ligand for ASGPR, into an LNP, Verve was able to efficiently and safely deliver a base editor to the liver in a mouse model of HoFH. Verve’s proprietary GalNAc-LNP was designed using novel chemical ligand compositions and a potent low ligand surface density, which is designed to optimize recognition and binding to ASGPRs. In addition, the formulation has been developed using a scalable process with favorable manufacturing properties similar to standard LNPs. Data presented demonstrate: High efficiency liver delivery of an adenine base editor targeting ANGPTL3 in both LDLR heterozygous and homozygous deficient mouse models; Low GalNAc-lipid content with 0.05 mol% leading to maximal liver editing in an LDLR knockout model; A scalable process of incorporating the GalNAc ligand into the LNP with near-homogenous distribution of GalNAc ligand; and Potent editing in vivo regardless of the LDLR status of the mouse. Verve is advancing a gene editing program that targets ANGPTL3, a gene known to regulate blood LDL-C and triglycerides. Such a program would have potential indications in both HoFH and in heterozygous familial hypercholesterolemia. Verve is designing this program to utilize a GalNAc-modified LNP encapsulating an mRNA encoding a base editor and a gRNA targeting the ANGPTL3 gene. The company’s program is currently in the lead optimization stage, and the company expects to name its development candidate and initiate IND-enabling studies in 2022.