Inhibition of PCSK9 with polypurine reverse hoogsteen hairpins: A novel gene therapy approach DOI Creative Commons
Ester López-Aguilar, Silvia Cecilia Pacheco-Velázquez, Maria Antònia Busquets

et al.

Biochemical Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 116976 - 116976

Published: May 1, 2025

PCSK9 is a therapeutic target for hypercholesterolemia. Though different strategies to inhibit PCSK9, such as monoclonal antibodies, small molecules, or nucleic acid drugs are available, the need safer and inexpensive interventions remains. We developed time-, cost-, resource- efficient silencing system using Polypurine Reverse Hoogsteen (PPRH) hairpins PCSK9. To achieve silencing, we designed two PPRHs targeting at exon 9 (HpE9) 12 (HpE12). The binding capabilities of were measured by EMSA: Kd values 7.86 x 10-8 M 7.58 10-7 HpE9 HpE12, respectively. complexed with cationic polymer jetPEI forming particles 167 nm characterized Dynamic Light Scattering. gene protein expression was evaluated upon transfections HepG2 cells HpE12. effectively reduced mRNA levels (63 % 74 respectively) (by 76 87 %) 24 h. Human overexpressing mice receiving single injection HpE12 decreased plasma 50 day three post returned baseline fifteen. Plasma cholesterol 47 three. Mice did not exhibit changes in body weight, liver enzymes pro-inflammatory markers when compared injected alone. Therefore, PPRH technology emerges an innovative based approach that effective, cost-efficient easy develop, inhibition

Language: Английский

Inhibition of PCSK9 with polypurine reverse hoogsteen hairpins: A novel gene therapy approach DOI Creative Commons
Ester López-Aguilar, Silvia Cecilia Pacheco-Velázquez, Maria Antònia Busquets

et al.

Biochemical Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 116976 - 116976

Published: May 1, 2025

PCSK9 is a therapeutic target for hypercholesterolemia. Though different strategies to inhibit PCSK9, such as monoclonal antibodies, small molecules, or nucleic acid drugs are available, the need safer and inexpensive interventions remains. We developed time-, cost-, resource- efficient silencing system using Polypurine Reverse Hoogsteen (PPRH) hairpins PCSK9. To achieve silencing, we designed two PPRHs targeting at exon 9 (HpE9) 12 (HpE12). The binding capabilities of were measured by EMSA: Kd values 7.86 x 10-8 M 7.58 10-7 HpE9 HpE12, respectively. complexed with cationic polymer jetPEI forming particles 167 nm characterized Dynamic Light Scattering. gene protein expression was evaluated upon transfections HepG2 cells HpE12. effectively reduced mRNA levels (63 % 74 respectively) (by 76 87 %) 24 h. Human overexpressing mice receiving single injection HpE12 decreased plasma 50 day three post returned baseline fifteen. Plasma cholesterol 47 three. Mice did not exhibit changes in body weight, liver enzymes pro-inflammatory markers when compared injected alone. Therefore, PPRH technology emerges an innovative based approach that effective, cost-efficient easy develop, inhibition

Language: Английский

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