Nanotherapeutics to reverse matrix pathophysiology in small aortic aneurysms

Project: Research

Investigators

  • Sarah Carney (PI)

Description

The goal of this pre-doctoral fellowship project is to investigate an innovative gene silencing nanotherapy for elastic matrix regenerative repair of abdominal aortic aneurysms (AAAs), localized aortal expansions which slowly grow to fatal rupture. There are no non-surgical treatments to reverse AAA pathophysiology. Chronic enzymatic breakdown of the elastic matrix in the AAA wall drives AAA growth, is naturally irreversible, and there are no approaches to reverse this. We have found inhibition of the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), upregulated in AAAs, to strongly correlate with decreases in elastolytic matrix metallopreotease (MMPs)-2 and -9 and increased elastic matrix neoassembly and crosslinking. In this project, I will investigate the benefits of attenuating JNK-2 gene (JNK2) via delivery of small interfering RNA (siRNA) to stimulating elastic matrix regeneration in a proteolytic milieu. Since cell uptake of naked siRNA is poor, the siRNA will be complexed with a cell penetrating carrier, polyethyleneimine (PEI). The PEI-siRNA will be locally delivered to the AAA wall from intravenously injected biodegradable polyethylene glycol polylactic-co-glycolic acid (PEG-PLGA) nanoparticles (NPs) we have developed, that provide pro-elastogenic and anti-proteolytic properties spate from effects due to released active agent. The NPs will be actively targeted with peptides that bind cathepsin K, a serine protease overexpressed by aneurysmal SMCs in the AAA wall. The research project will test hypotheses that a) JNK-2 PEI-siRNA when released within AAAs via targeted NPs will silence JNK-2 mRNA in the AAA wall, and b) will stimulate elastic matrix regeneration towards restoring wall elastin homeostasis. The specific aims (SAs) are: SA1. Identify conditions of PEI-SIRNA complexing conducive to safe JNK-2 mRNA knockdown and which provide the greatest stimulus to elastic matrix neoassembly in rat AAA SMC cultures, SA2. a) Develop NP formulations for sustained release of functional PEI-siRNA and b) assess synergy of effect between PEI-siRNA and NP carriers in rat AAA SMC cultures, and SA3. Demonstrate efficient targeting and retention of PEI-siRNA releasing NPs in the AAA wall in a rat model and generate initial evidence of effectiveness in restoring elastin homeostasis. This investigation of a minimally invasive matrix regenerative nanotherapy for AAAs aligns with AHA's mission to develop new non-surgical approaches for devastating vasc
Award amount$62,032.00
Award date01/01/2020
Program typePredoctoral Fellowship
Award ID20PRE35120023
Effective start/end date01/01/202012/31/2021
StatusActive