ANGPTL3 Base Editor Delivered via Internally Developed GalNAc-LNPs Potently Reduced Blood ANGPTL3 Protein by 94-97% in a Novel NHP Model of Homozygous Familial Hypercholesterolemia
GalNAc-LNP Delivery of ANGPTL3 Base Editor Led to Potent Editing in both LDLR-Deficient and Normal NHP Livers, Supporting Potential Broad Applicability
CAMBRIDGE, Mass., Nov. 09, 2021 (GLOBE NEWSWIRE) -- Verve Therapeutics, a biotech company pioneering a new approach to the care of cardiovascular disease with single-course gene editing medicines, today announced new preclinical data highlighting the ability of its internally developed GalNAc-lipid nanoparticle (LNP) technology to deliver a base editor targeting ANGPTL3 to the livers of non-human primates (NHPs). The data demonstrate that delivery of Verve’s ANGPTL3 base editor via its proprietary GalNAc-LNP led to potent reductions in blood ANGPTL3 protein levels and disease-driving low-density lipoprotein cholesterol (LDL-C) in a novel NHP model of homozygous familial hypercholesterolemia (HoFH). HoFH is a rare genetic subtype of atherosclerotic cardiovascular disease (ASCVD) characterized by extremely high blood LDL-C. The full data will be published in a manuscript on bioRxiv.org.
Verve is advancing its in vivo ANGPTL3 base editing program for the treatment of ASCVD indications, including HoFH. In HoFH patients, delivery of base editors to the liver with standard LNPs is challenging due to deficiency of LDL receptor (LDLR) protein, which is known to mediate LNP uptake. To address this challenge, Verve has developed proprietary LNPs with the addition of a GalNAc ligand. These GalNAc-LNPs are designed to bind to asialoglycoprotein receptors (ASGPRs), which bypass LDLR, thereby enabling uptake into the liver in HoFH patients. Today’s data build upon previously reported findings from an HoFH mouse model showing efficient and safe delivery of base editors leveraging the company’s GalNAc-LNPs and now demonstrate the effectiveness of this delivery technology in NHPs that lack LDLR.
“The ANGPTL3 gene is a well-validated genetic target for lowering blood lipids, such as LDL-C, a key driver of ASCVD. Base editing of ANGPTL3 has the potential to offer a new treatment approach that could benefit patients across multiple different cardiovascular indications,” said Andrew Bellinger, M.D., Ph.D., chief scientific officer and chief medical officer of Verve. “Leveraging our innovation in GalNAc-LNPs, we have generated evidence supporting application of our ANGPTL3 base editing program in a patient population for which standard LNP delivery is not possible, expanding the potential reach of our single-course gene editing therapies. These NHP data increase our confidence in the translation of therapeutic impact to patients with HoFH and support the potential of our approach to treat a broad range of ASCVD indications.”
To evaluate the company’s ANGPTL3 program for HoFH using its GalNAc-LNP approach for delivery, Verve implemented a multi-step strategy assessing delivery capabilities, editing potential and addressable disease states. The process and findings include:
- Development of a Novel NHP Disease Model of HoFH with LDLR Deficiency: Verve created an NHP model of HoFH by editing the LDLR gene and eliminating its expression in the livers of NHPs, leveraging Cas9 and a dual guide RNA (gRNA) strategy encapsulated in standard LNPs that deliver to the liver.
- Administration of the spCas9-dual gRNA LNP efficiently disrupted the LDLR gene, leading to nearly 70% whole liver DNA editing at the LDLR gene, resulting in an approximately 94% reduction in LDLR protein in the liver and a substantial rise in blood LDL-C.
- Precise Editing of ANGPTL3 via Base Editor Delivered with a GalNAc-LNP: Verve then evaluated its ANGPTL3-targeted base editor delivered via its GalNAc-LNPs in its NHP model of HoFH.
- Following administration of two different internally developed GalNAc-LNP formulations, Verve observed approximately 94% (n=3) and 97% (n=3) reductions in blood ANGPTL3 protein, and substantial reductions in LDL-C of nearly 100mg/dL, which was an approximately 35% reduction from baseline.
- Application of GalNAc-LNP Delivery to Both LDLR-deficient and Normal Livers: Finally, to assess the potential broad utility of its GalNAc-LNP for delivery of an ANGPTL3-targeted base editor, Verve conducted a study evaluating delivery efficiency of its ANGPTL3 base editor using both a GalNAc-LNP and a standard LNP without GalNAc in wild-type NHPs with normal livers.
- Verve’s GalNAc-LNP led to an approximately 89% reduction in ANGPTL3 protein in wild-type NHPs compared with an approximately 74% reduction with a standard LNP, which suggests that GalNAc-LNP delivery may be utilized in indications where LDLR is present.
Verve is conducting additional preclinical studies with its GalNAc-LNP technology and plans to select a development candidate for its ANGPTL3 program and initiate investigational new drug-enabling studies in 2022.
About Verve Therapeutics
Verve Therapeutics, Inc. (Nasdaq: VERV) is a genetic medicines company pioneering a new approach to the care of cardiovascular disease, transforming treatment from chronic management to single-course gene editing medicines. The company’s initial two programs target PCSK9 and ANGPTL3, genes that have been extensively validated as targets for lowering blood lipids such as low-density lipoprotein cholesterol (LDL-C), a root cause of cardiovascular disease. Verve’s lead product candidate, VERVE-101, is designed to permanently turn off the PCSK9 gene in the liver in order to disrupt blood PCSK9 protein production and thereby durably reduce blood LDL-C levels, with the goal of reducing a patient’s risk for cardiovascular disease. VERVE-101, currently in IND-enabling studies, is being developed initially for the treatment of patients with heterozygous familial hypercholesterolemia, a potentially fatal genetic heart disease. For more information, please visit www.VerveTx.com.
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