About the Article
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[This article belongs to Volume - 69, Issue - 9]
Published on : 2024-09-05 12:41:12
Article Code: AMJ-05-09-2024-12298
Title : Base Editing of the PCSK9 Gene in Human Hepatocytes via Lipid Nanoparticle-Delivered Adenine Base Editors: A Non-Viral Approach for Familial Hypercholesterolemia
Author(s) : Dr. Alexander Petrov, Dr. Amina Diallo
Abstract :
Familial hypercholesterolemia (FH) is characterized by loss-of-function mutations in the LDL receptor pathway.
Current therapies require lifelong administration. We report a non-viral gene editing strategy employing adenine
base editors (ABE8e) packaged in liver-targeted lipid nanoparticles (LNPs) to precisely disrupt the PCSK9 translational
start site in human hepatocytes. In humanized PCSK9 mouse models and primary human hepatocyte spheroids, a
single intravenous administration achieved 65% editing efficiency at the target locus, resulting in 80% reduction of
plasma PCSK9 protein and 50% lowering of LDL-cholesterol levels sustained for 20 weeks. Off-target analysis via
GUIDE-seq detected no significant unintended mutations. Deep sequencing confirmed permanent hepatocyte DNA
modification without episomal persistence. This direct base editing platform offers a potential one-time curative
intervention for autosomal dominant hypercholesterolemia.