[HTML][HTML] Long-term stable reduction of low-density lipoprotein in nonhuman primates following in vivo genome editing of PCSK9

L Wang, C Breton, CC Warzecha, P Bell, H Yan, Z He… - Molecular Therapy, 2021 - cell.com
L Wang, C Breton, CC Warzecha, P Bell, H Yan, Z He, J White, Y Zhu, M Li, EL Buza, D Jantz…
Molecular Therapy, 2021cell.com
Gene disruption via programmable, sequence-specific nucleases represents a promising
gene therapy strategy in which the reduction of specific protein levels provides a therapeutic
benefit. Proprotein convertase subtilisin/kexin type 9 (PCSK9), an antagonist of the low-
density lipoprotein (LDL) receptor, is a suitable target for nuclease-mediated gene disruption
as an approach to treat hypercholesterolemia. We sought to determine the long-term
durability and safety of PCSK9 knockdown in non-human primate (NHP) liver by adeno …
Gene disruption via programmable, sequence-specific nucleases represents a promising gene therapy strategy in which the reduction of specific protein levels provides a therapeutic benefit. Proprotein convertase subtilisin/kexin type 9 (PCSK9), an antagonist of the low-density lipoprotein (LDL) receptor, is a suitable target for nuclease-mediated gene disruption as an approach to treat hypercholesterolemia. We sought to determine the long-term durability and safety of PCSK9 knockdown in non-human primate (NHP) liver by adeno-associated virus (AAV)-delivered meganuclease following our initial report on the feasibility of this strategy. Six previously treated NHPs and additional NHPs administered AAV-meganuclease in combination with corticosteroid treatment or an alternative AAV serotype were monitored for a period of up to 3 years. The treated NHPs exhibited a sustained reduction in circulating PCSK9 and LDL cholesterol (LDL-c) through the course of the study concomitant with stable gene editing of the PCSK9 locus. Low-frequency off-target editing remained stable, and no obvious adverse changes in histopathology of the liver were detected. We demonstrate similar on-target nuclease activity in primary human hepatocytes using a chimeric liver-humanized mouse model. These studies demonstrate that targeted in vivo gene disruption exerts a lasting therapeutic effect and provide pivotal data for safety considerations, which support clinical translation.
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