Understanding Delivery Systems

Gene editing begins with the transport of messenger RNA (mRNA) and guide RNA (gRNA) molecules into a target cell. The molecules need a delivery system to bring them through the body to the desired location in order to perform the edit within the target gene.

Among current delivery system options, a non-viral approach that uses LNPs is a proven method with a potentially superior safety profile. LNPs can bypass the main biological barriers of a cell, therefore providing an effective option for delivering mRNA and gRNA molecules into cells for base editing. 

Verve is leveraging LNPs to deliver its base editors for its lead programs to the liver, including a licensed LNP for delivery of VERVE-101 and a proprietary, internally developed LNP for delivery of VERVE-102 and VERVE-201, our GalNAc-LNP.

Our team has developed a novel liver delivery technology: GalNAc-LNP. We initially developed this system for VERVE-201 to address an important challenge with delivery to the liver in people with homozygous familial hypercholesterolemia (HoFH): individuals with HoFH do not have LDL receptors on the surface of their liver cells, making standard LNP delivery ineffective.

Similar to LNP delivery, GalNAc-LNP encapsulates an mRNA and gRNA, but it features a GalNAc targeting ligand. This ligand helps the system bind to the asialoglycoprotein receptor (ASGPR), in addition to the low-density lipoprotein receptor, on liver cells and deliver the gene editor into the liver. 

We believe GalNAc provides a delivery platform for patients with HoFH as well as heterozygous familial hypercholesterolemia (HeFH) and may be applicable in other indications where liver-directed delivery of gene editors is advantageous. In nonclinical studies of our product candidates targeting ANGPTL3 and PCSK9, GalNAc-LNP delivery demonstrated effective in vivo liver gene editing and greater reductions of the target protein than with LNP delivery.