{"id":"doi:10.1038/s41467-023-37465-1","kind":"article","title":"GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy","authors":["Kasiewicz LN","Biswas S","Beach A","Ren H","Dutta C","Mazzola AM","Rohde E","Chadwick A","Cheng C","Garcia SP","Iyer S","Matsumoto Y","Khera AV","Musunuru K","Kathiresan S","Malyala P","Rajeev KG","Bellinger AM"],"author_count":18,"year":2023,"published":"2023-05-15","venue":"Nature communications","cited_by":138,"doi":"10.1038/s41467-023-37465-1","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41467-023-37465-1","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41467-023-37465-1","updated":null,"pmid":"37188660","pmcid":"PMC10185539","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC10185539/pdf","abstract":"Lipid nanoparticles have demonstrated utility in hepatic delivery of a range of therapeutic modalities and typically deliver their cargo via low-density lipoprotein receptor-mediated endocytosis. For patients lacking sufficient low-density lipoprotein receptor activity, such as those with homozygous familial hypercholesterolemia, an alternate strategy is needed. Here we show the use of structure-guided rational design in a series of mouse and non-human primate studies to optimize a GalNAc-Lipid nanoparticle that allows for low-density lipoprotein receptor independent delivery. In low-density lipoprotein receptor-deficient non-human primates administered a CRISPR base editing therapy targeting the ANGPTL3 gene, the introduction of an optimized GalNAc-based asialoglycoprotein receptor ligand to the nanoparticle surface increased liver editing from 5% to 61% with minimal editing in nontargeted tissues. Similar editing was noted in wild-type monkeys, with durable blood ANGPTL3 protein reduction up to 89% six months post dosing. These results suggest that GalNAc-Lipid nanoparticles may effectively deliver to both patients with intact low-density lipoprotein receptor activity as well as those afflicted by homozygous familial hypercholesterolemia.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy\" by Kasiewicz LN, Biswas S, Beach A et al., https://doi.org/10.1038/s41467-023-37465-1, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified.","topics":[{"slug":"gene-editing-therapies","name":"CRISPR & Gene-Editing Therapies","domain_slug":"medicine"}],"cited_in_dossiers":[]}