OC 39.1 - Age-associated increases in PAI-1 silenced with siRNA-lipid nanoparticles reduce thrombosis

Monday, June 24, 2024

09:30 – 09:45 ICT

Room: 208 A-D

Presenting Author(s)

Francesca Ferraresso, BSc

Graduate Student
University of British Columbia
Vancouver, British Columbia, Canada

Co-Author(s)

MS

Monica Seadler

Surgery Residence
Versiti Blood Research Institute
Milwaukee, Wisconsin, United States
TC

Taylor Chen

Medical Student
Medical College of Wisconsin
Milwaukee, Wisconsin, United States
Woosuk S. Hur, PhD

University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
GR

Geoffrey Rodriguez

Medical Student
Medical college of Wisconsin
Milwaukee, Wisconsin, United States
LK

Laura Ketelboeter

Research scientist
Versiti blood research institute
Milwaukee, Wisconsin, United States
LJ

Lih Jiin Juang

Chief scientific officer
SeraGene Therapeutics
Vancouver, British Columbia, Canada
AS

Amy Strilchuk

Post-Doctoral fellow
University of Toronto
Toronto, Ontario, Canada
MD

Mitchell Dyer

Professor and surgeon
Medical College of Wisconsin
Milwaukee, Wisconsin, United States
Matthew Flick

Professor
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
Christian J. Kastrup

Senior Investigator
Versiti Blood Research Institute
Milwaukee, Wisconsin, United States

Background: Plasminogen activator inhibitor 1 (PAI-1) plays a role in many pathologies including thrombosis, diet-induced obesity, and various age-associated diseases. Circulating PAI-1 increases with age, which contributes to the increased thrombotic risk associated with aging. Deficiency in PAI-1 protects patients from cardiovascular morbidity and extends human and murine lifespan. Previously developed PAI-1 inhibitors have stalled in clinical trials, presumably due to low specificity and rapid clearance. RNA gene therapy is a methodology to regulate the levels of proteins that are not amenable to traditional small-molecule or antibody-based therapies.

Aims: To develop an siRNA-lipid nanoparticle (LNP) agent which knocks down PAI-1 in the liver to modulate its circulating levels long-term and test it in young and aged mouse models.

Methods: Encapsulating siRNA agents in LNPs allows delivery to the liver with the advantage of being long-acting and highly specific for its target. We screened various siRNA sequences and PAI-1 knockdown was analyzed based on plasma antigen and mRNA expression levels in the liver, including in young, aged and obese mice. The impact on thrombosis was assessed in an inferior vena cava (IVC) thrombosis model.

Results: A dose of siPAI-1 resulted in a 90% knockdown of PAI-1 plasma lasting 10 days without overt toxicity. siPAI-1 normalized the supraphysiologic concentration of PAI-1 in elderly mice, and decreased thrombus weight in adult and elderly mice that underwent ligation of the IVC. siPAI-1 increased the probability of survival of aged mice 4 days post-IVC ligation. Hepatic PAI-1 mRNA expression in diet-induced obese mice was >10-times greater than in healthy mice and it was exponentially correlated with the mouse body weight.

Conclusion(s): An injection of siRNA encapsulated in LNPs can potently knockdown PAI-1 in plasma for multiple weeks. This agent is a potential safe and long-term anticoagulant approach to knockdown the excess production of PAI-1 during aging and in age-related diseases.