A GalNAc-Lipid nanoparticle enables efficient non-LDLR dependent hepatic delivery of a CRISPR base editing therapy

Lipid nanoparticles (LNPs) have demonstrated utility in hepatic delivery of a range of therapeutic modalities and typically deliver their cargo via low-density lipoprotein receptor (LDLR) mediated endocytosis. For patients lacking sufficient LDLR activity, such as those with homozygous familial hypercholesterolemia (HoFH), an alternate strategy is needed. Here, we describe the use of structure-guided rational design in a series of mouse and non-human primate (NHP) studies to optimize a GalNAc-LNP that allows for LDLR-independent delivery. In LDLR-deficient NHPs administered a CRISPR base editing therapy targeting the ANGPTL3 gene, the introduction of an optimized GalNAc-based asialoglycoprotein receptor (ASGPR) ligand to the LNP surface increased liver editing from 5% to 60% with minimal editing in nontargeted tissues. Beyond LDLR-deficient NHPs, a similar degree of editing was noted in wild-type NHPs, with durable reduction of blood ANGPLT3 protein of up to 89% six months post dosing. These results suggest that GalNAc-LNPs may be well-suited for delivery to both patients with intact LDLR activity as well as those afflicted by HoFH.