RNA-therapy for targeting advanced atherosclerotic plaques

Atherosclerosis is the leading cause of death globally and in Australia, where its responsible for 1 in 4 deaths. Despite such high disease burden, existing therapeutic management of atherosclerosis can be ineffective in up to 50% of patients. Current optimal medical therapy focuses on lipid lowering, but its use in patients can be limited by side effects. Recent focus on repurposing anti-inflammatory therapies for atherosclerosis gave equivocal results also due to life-threatening side effects. Hence, there remains an outstanding need for a novel, effective and safe therapy to treat atherosclerosis.

In this project, we aim to develop proof-of-concept for an innovative cell-based therapy to treat atherosclerosis, a disease in which the rupture of fatty plaques causes heart attacks and strokes. The stability of a plaque largely determines its risk of rupture. We have discovered that increasing a specific signalling pathway called TGFβ and NOTCH3 in plaque cells increases stability of the plaque, protecting it against rupture. We are seeking funding to advance our discovery onto the next stage of clinical translation, that is, to conduct RAN-based therapeutic studies on increasing TGFβ and NOTCH3 therapeutically to increase plaque stability. We collaborate with key next-step partners, USyd and UNSW (RNA institute), to develop RNA based technique to enhance TGFβ and NOTCH3 expression in inflamed plaque cells. These are detailed in the aims. Our collaborators, at HRI and University of Sydney will facilitate RNA loading and its delivery into pre-clinical animal models. Together we will evaluate which RNA molecule provide best efficacy& safety pre-clinically to progress onto future translation.

The first and second aim will be to test two methods of utilising the RNA particles to promote TFGβ-NOTCH3 signalling in plaque.

Aim 1: To identify and perform screening for lncRNA on in vitro vascular cell culture system that can induce beneficial effects.

Aim 2: Assess the efficacy of identified RNA molecule to promote plaque stability and determine if any side-effects occur on adjacent cells and body organs.

This project intends to deliver proof-of-concept of preclinical efficacy and safety for delivery of RNA based NOTCH3-promoting drugs. Outcome from the aims will help to provide the best therapeutic effects and least adverse impact on adjacent cells and body organs.

The group will then scale-up manufacturing of RNA molecule under GLP and GMP conditions and conduct pre-clinical efficacy, safety and toxicology studies based on the methodology deemed most successful in Step (1). It will establish long-term biosafety through pharmacokinetic and pharmacodynamic studies and de-risk this technology. (2) The Fluxomics Facility Centre at HRI will support drug profiling, release and pharmacological studies. Our established animal breeding program at Heart Research Institute will provide animals to support these trials. Our team will ensure that all necessary regulatory documentation is completed at all steps to ensure transparency and smooth translation process.

In vitro cell culture, in vivo mouse models, cardiovascular genetics, Bioinformatics, molecular biology, confocal microscopy and RNA-sequencing.