GalNAc-Lipid nanoparticles enable non-LDLR dependent hepatic delivery of a CRISPR base editing therapy

Lisa N. Kasiewicz, Souvik Biswas, Aaron Beach, Huilan Ren, Chaitali Dutta, Anne Marie Mazzola, Ellen Rohde, Alexandra Chadwick, Christopher Cheng, Sara P. Garcia, Sowmya Iyer, Yuri Matsumoto, Amit V. Khera, Kiran Musunuru, Sekar Kathiresan, Padma Malyala, Kallanthottathil G. Rajeev and Andrew M. Bellinger ()
Additional contact information
Lisa N. Kasiewicz: Verve Therapeutics, 201 Brookline Avenue, Suite 601
Souvik Biswas: Verve Therapeutics, 201 Brookline Avenue, Suite 601
Aaron Beach: Verve Therapeutics, 201 Brookline Avenue, Suite 601
Huilan Ren: Verve Therapeutics, 201 Brookline Avenue, Suite 601
Chaitali Dutta: Verve Therapeutics, 201 Brookline Avenue, Suite 601
Anne Marie Mazzola: Verve Therapeutics, 201 Brookline Avenue, Suite 601
Ellen Rohde: Verve Therapeutics, 201 Brookline Avenue, Suite 601
Alexandra Chadwick: Verve Therapeutics, 201 Brookline Avenue, Suite 601
Christopher Cheng: Verve Therapeutics, 201 Brookline Avenue, Suite 601
Sara P. Garcia: Verve Therapeutics, 201 Brookline Avenue, Suite 601
Sowmya Iyer: Verve Therapeutics, 201 Brookline Avenue, Suite 601
Yuri Matsumoto: Verve Therapeutics, 201 Brookline Avenue, Suite 601
Amit V. Khera: Verve Therapeutics, 201 Brookline Avenue, Suite 601
Kiran Musunuru: Perelman School of Medicine at the University of Pennsylvania
Sekar Kathiresan: Verve Therapeutics, 201 Brookline Avenue, Suite 601
Padma Malyala: Verve Therapeutics, 201 Brookline Avenue, Suite 601
Kallanthottathil G. Rajeev: Verve Therapeutics, 201 Brookline Avenue, Suite 601
Andrew M. Bellinger: Verve Therapeutics, 201 Brookline Avenue, Suite 601

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37465-1

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