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

Autor: Kasiewicz LN; Verve Therapeutics, 201 Brookline Avenue, Suite 601, Boston, MA, 02215, USA., Biswas S; Verve Therapeutics, 201 Brookline Avenue, Suite 601, Boston, MA, 02215, USA., Beach A; Verve Therapeutics, 201 Brookline Avenue, Suite 601, Boston, MA, 02215, USA., Ren H; Verve Therapeutics, 201 Brookline Avenue, Suite 601, Boston, MA, 02215, USA., Dutta C; Verve Therapeutics, 201 Brookline Avenue, Suite 601, Boston, MA, 02215, USA., Mazzola AM; Verve Therapeutics, 201 Brookline Avenue, Suite 601, Boston, MA, 02215, USA., Rohde E; Verve Therapeutics, 201 Brookline Avenue, Suite 601, Boston, MA, 02215, USA., Chadwick A; Verve Therapeutics, 201 Brookline Avenue, Suite 601, Boston, MA, 02215, USA., Cheng C; Verve Therapeutics, 201 Brookline Avenue, Suite 601, Boston, MA, 02215, USA., Garcia SP; Verve Therapeutics, 201 Brookline Avenue, Suite 601, Boston, MA, 02215, USA., Iyer S; Verve Therapeutics, 201 Brookline Avenue, Suite 601, Boston, MA, 02215, USA., Matsumoto Y; Verve Therapeutics, 201 Brookline Avenue, Suite 601, Boston, MA, 02215, USA., Khera AV; Verve Therapeutics, 201 Brookline Avenue, Suite 601, Boston, MA, 02215, USA., Musunuru K; Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA., Kathiresan S; Verve Therapeutics, 201 Brookline Avenue, Suite 601, Boston, MA, 02215, USA., Malyala P; Verve Therapeutics, 201 Brookline Avenue, Suite 601, Boston, MA, 02215, USA., Rajeev KG; Verve Therapeutics, 201 Brookline Avenue, Suite 601, Boston, MA, 02215, USA., Bellinger AM; Verve Therapeutics, 201 Brookline Avenue, Suite 601, Boston, MA, 02215, USA. abellinger@vervetx.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 May 15; Vol. 14 (1), pp. 2776. Date of Electronic Publication: 2023 May 15.
DOI: 10.1038/s41467-023-37465-1
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz: