Dr Mary Kavurma of the Heart Research Institute is conducting research to find a new treatment to prevent limb amputation due to cardiovascular disease, through the TRAIL mechanism.

The challenge:

Cardiovascular disease affects one in every six Australians. It can manifest in the form of Peripheral Artery Disease (PAD), where blood flow to the limbs is reduced due to narrowed arteries. When circulation is cut off, the limb develops gangrene and starts to decay and die.

Currently, there is no cure for gangrene. The only treatment option is to amputate the affected limb to prevent the gangrene from spreading further.

Every three hours in Australia, one person has an arm or leg amputated due to PAD.

Additionally, people with type 2 diabetes are three to four times more likely to develop cardiovascular conditions, including PAD. Diabetes-related amputations and associated costs place a $875M burden on the Australian healthcare system every single year.

The solution:

Dr Mary Kavurma and the team at the Heart Research Institute have found that TRAIL (Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand), a naturally occurring molecule, has shown it can stimulate the growth of new blood vessels and dramatically improve blood flow to the limbs in animal experiments.

This discovery offers hope of a potential new treatment pathway for PAD. If a drug could be identified that activates the TRAIL mechanism in people with PAD, so new blood vessels grew, it could bypass the narrowed arteries and restore blood flow to the limbs.

Pen CS caught up with Dr Mary Kavurma to find out more about her research.

Q. Can you tell us a bit about your background?

I always really loved science, particularly biology and chemistry. I did a BSc at Macquarie University and while an undergraduate student I was lucky enough to receive a CSIRO Student vacation research scholarship; this is where I fell in love with research. I did Honours at UNSW, followed by a PhD in pathology of cardiovascular disease.  I then went abroad to the UK on an NHMRC CJ Martin postdoctoral Fellowship, coming back to UNSW, where I established a small team. I then moved to the Heart Research Institute (HRI) as Group Leader of the Vascular Complications team. In addition to my lab, I wear a management hat and am Associate Director of Scientific Management and Education. I also have a Senior Lecturer affiliation at Sydney University.

My most significant contributions to research are in cell biology of atherosclerosis, particularly relating to mechanisms of vascular smooth muscle and endothelial cell proliferation, differentiation and death.

Q. Can you tell us a bit about this study?

Peripheral artery disease (PAD) is a condition where narrowed arteries reduce blood flow to the lower limbs and is a major risk factor for lower-limb amputation. In Australia, a limb is amputated every 3 h due to cardiovascular disease, and this is increased to every 30 min if the patient also has diabetes. The total cost to the economy is >$875M/year (Diabetes Australia). Amputations do not fix the underlying problem (the atherosclerotic vessel), but merely remove dead or dying tissue. Because of this, PAD patients can have multiple presentations with gangrene, requiring recurrent amputations, each of which increases their risk of myocardial infarction. Alarmingly, with the obesity and diabetes pandemic, the disease burden is rising and requires urgent action. However, no significant advances in revascularisation techniques have occurred in the last 2 decades. Additional treatments are therefore urgently needed.

My laboratory discovered an exciting new mechanism that stimulates new blood vessel formation (or angiogenesis) in PAD in mice, restoring blood flow, and preserving tissue survival and function. We showed that this is mediated by a naturally-occuring molecule called tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL).

These findings are significant because they provide new knowledge as to how TRAIL regulates blood vessel formation and lay the foundations for therapeutic use in people with PAD, which could be extended to other ischaemic vascular diseases e.g. coronary heart disease.

Q. What are you hoping to achieve with this study? What are the possible real world implications?

TRAIL was discovered for its unique ability to selectively kill cancer cells and was hailed a cancer therapeutic. Clinical trials for TRAIL in this field have been disappointing, with very little survival benefit observed in cancer patients.

In complete contrast to its role in cancer, work in my laboratory uncovered entirely novel functions of TRAIL in the vasculature. We have shown that an injection of TRAIL into the muscle of mice with PAD stimulates new blood vessel development, bypassing the blocked blood vessel. Findings from my lab present an opportunity for a new approach to therapy in people suffering from PAD.

We are in a unique position to fast track the use of TRAIL by repurposing or modifying it for PAD in humans. An approach to increase blood vessel networks and blood perfusion by injection of therapeutics to improve micro vessel function would be life changing; a lot less amputees and better quality of life for these patients.

Q. What made you want to focus on Cardiovascular Disease?

Cardiovascular disease is the world’s biggest killer. Currently in Australia, a person suffers from a heart attack every 10 min. We need to understand more about the pathogenesis of this very complex disease in order to find new treatment options for patients.

Q. What were the discoveries that have lead up to your current work?

During my PhD, I studied proteins which act as important switches and trigger cells to die.  Cell death in atherosclerosis is a major problem, as it can weaken the walls of diseased blood vessels, promoting the formation of blood clots.  Following my PhD, I was successful in obtaining a prestigious NHMRC CJ Martin and spent 2 years at Cambridge University.  I studied the mechanisms that make cells grow abnormally in atherosclerosis, leading to abnormal thickening of the walls of blood vessels and contributing to their blockage. During my postdoc in Cambridge, I became interested in TRAIL. Since my return, my lab’s work has revolutionalised our understanding of the molecules that control cell growth and death in atherosclerosis, but also in the formation of new blood vessels.

Q. What has been the biggest challenge so far?

The biggest challenge is the lack of funding. Funding for medical research is cut every year. Currently, the success rate is about 13%.

Bench to beside is what we strive for in our research, however, this takes a long time and is incredibly expensive.

Q. What are your next steps for this research study?

There are a number of different angles that we are currently looking at. One is to identify small molecule activators of TRAIL; drugs that are already being used as treatment for other indications, to see if we can find alternate medications for the treatment of PAD.

 

If you wish to find out more information about this research study, please contact us here.

 

The Wenkart Foundation is proud to be a supporter of this research study.