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- Title
GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy.
- Authors
Kasiewicz, Lisa N.; Biswas, Souvik; Beach, Aaron; Ren, Huilan; Dutta, Chaitali; Mazzola, Anne Marie; Rohde, Ellen; Chadwick, Alexandra; Cheng, Christopher; Garcia, Sara P.; Iyer, Sowmya; Matsumoto, Yuri; Khera, Amit V.; Musunuru, Kiran; Kathiresan, Sekar; Malyala, Padma; Rajeev, Kallanthottathil G.; Bellinger, Andrew M.
- 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. Kasiewicz et al. describe a structure-guided rational design approach to optimize a new GalNAc-Lipid nanoparticle that enables delivery of a base editing therapy in both low-density lipoprotein receptor-deficient and wild-type nonclinical models.
- Subjects
GENOME editing; HOMOZYGOUS familial hypercholesterolemia; FAMILIAL hypercholesterolemia; CRISPRS; LIPOPROTEIN receptors; LOW density lipoproteins
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-37465-1