Targeting IRAP: a novel treatment to help stabilise existing abdominal aortic aneurysms

Aortic aneurysms are a degenerative disease that generally occur in the abdominal region and affect people over the age of 65 years. The disease is usually a silent killer with a mortality rate over 90 percent. It is usually detected when a patient undergoes screening using CT or ultrasound for another complication such as a blocked artery. Currently there are no drugs that can stabilise existing abdominal aortic aneurysms (AAAs), with patients kept under surveillance to monitor the expansion of aneurysms until the diameter is ~5.5cm. At this point, surgical intervention is the only option.

Using ultrasound for preclinical drug trials

Preclinical studies in various mouse models have shown positive effects of a number of different drugs in preventing the development of AAAs. However, these drugs have not been successfully translated into the clinic.

A team of researchers from Monash Biomedicine Discovery Institute’s (BDI) Cardiovascular Disease group are using Monash Biomedical Imaging’s Vevo2100 Ultrasound in their preclinical trials of novel drugs that target and inhibit the activity of the enzyme, IRAP, and assess their effectiveness in stabilising established AAAs.

BDI’s Prof Robert Widdop, Dr Tracey Gaspari, and Kaki Fan used a mouse model infused with Angiotensin II for two weeks to induce AAA development. Once aneurysms were established, mice were then randomised to receive either vehicle or one of the novel drugs targeting IRAP for a further four-week period. Over this time, Monash Biomedical Imaging’s ultrasound imaging expert, Dr Ekaterina (Caty) Salimova used the Vevo2100 Ultrasound to monitor aneurysm development.

Ultrasound imaging and analysis were essential for this longitudinal study, which required imaging at different stages of the disease and treatment progression. Ultrasound imaging was chosen as it is quick, straightforward and the least invasive for mice.

The imaging modalities and analysis packages on the Vevo2100 Ultrasound also allowed for very high temporal and spatial resolution, as well as functional assessment of vessel compliance.

Next steps

Once the preliminary study establishing the importance of targeting IRAP to prevent AAA development and progression is completed, future studies will assess the beneficial effects of the novel IRAP inhibitors against current drugs that are undergoing clinical trial evaluation (e.g., ACE inhibitors and angiotensin receptor blockers). Importantly, as new compounds with better oral bioavailability are developed, these will be assessed with the hope that we will see these in clinical trials targeting AAA progression in the future.