At the Heart of Gene Therapy – Prof Victor Dzau

Dzau focused on discovering molecular and genetic mechanisms of diseases and translating these discoveries into clinical applications. His work has made a significant impact and improved health and medicine globally. In 2019, he was named an Honorary Citizen of Singapore — the highest level of honour bestowed to a foreign citizen conferred by the President of Singapore, for his contributions to the country’s health development.

[In this Q&A, Dzau shares with PRECISE his journey into academia and how it has shaped his research interests, alongside his experience developing a well-integrated and collaborative research programme involving public health and research institutions.]

Could you walk us through your research journey and what led you to apply gene therapy in cardiovascular disease research?

I was fortunate enough to go to McGill University in Canada for an undergraduate biology major, and then medical school. This is where my journey started. In medical school, I found the physiology course on cardiovascular physiology truly energising. It seemed to me like this was an area where medicine and science came together.

Fast forward many years later, our research pioneered the discipline of vascular medicine. Our work in cardiovascular medicine and genetics laid the foundation for the development of the class of lifesaving drugs known as ACE inhibitors, used globally to treat hypertension and heart failure.

We also pioneered gene therapy for vascular disease. More recently, our work on stem cell paracrine mechanisms and the use of microRNA in direct cardiac reprogramming provides novel insight into stem cell biology and regenerative medicine. There are multiple genetic contributors to cardiovascular diseases. It is important that we elucidate the genetic basis and mechanisms of the diseases so we can find better treatments or even cures.

Why was it important to explore the possibility of effective gene therapy specifically for cardiovascular disease?

There are multiple genetic abnormalities related to cardiovascular disease. It is important that we find markers to have better cures for cardiovascular diseases. When I went to Stanford in 1990, I became very interested in the potential of gene therapy and focused my research on developing gene therapy for cardiovascular diseases. This was timely as the genetic and molecular mechanisms of coronary artery disease, restenosis (recurrence of arterial blockage) and bypass graft failure were being understood and therefore were prime targets for gene therapy. My lab investigated the potential roles of antisense oligonucleotide, a type of synthetic DNA strand, and nitric oxide synthase gene to prevent conditions that can lead to the failure of vascular bypass grafts.

Although we took this work all the way to human phase III trials to prevent graft failure, the results were not positive, despite the encouraging results in phase I and phase II. We continued the work on gene therapy and developed the concept of protecting the ischemic myocardium, a method of maintaining optimum blood flow to the heart, which is still relevant today. More recently, my lab has been working on cardiac regeneration using microRNA.

Research does not always get translated into bedside applications. Can you provide insights on how to successfully transition discoveries in the lab into technologies that relate to public health?

In 2010, I published in Lancet the concept of “Bench to Bedside to Population” which highlighted the continuum of basic to translational research to clinical implementation in public and population health.  Translating research is very important as it is through this process that we can truly see if the findings we observe in animal models can be observed in human patients. Animal studies are good starting points, but clinical trials are needed to prove the efficacy of the treatment in humans and get FDA approval.

Public health can identify those who are at risk of cardiovascular disease so that one can implement preventive measures and early interventions. There is a lot of interest in applying technologies such as genomics to public health through the new field of Precision Public Health.

You have supported the idea of academic health centres (AHCs) as critical infrastructure in transforming medicine through innovation in an article published in The Lancet. In your opinion, how can the research infrastructure in Singapore’s research institutions be further strengthened and streamlined to support the NPM programme?

Singapore has made critical investments in biomedical research, AHC and public health. By investing in national initiatives like PRECISE, in cooperation with AHCs like Duke NUS and SingHealth and other research institutions, there is significant potential for making major scientific discoveries and clinical impacts.

Through the National Precision Medicine (NPM), PRECISE is leading the effort by studying existing and new cohorts, collecting biospecimens and data, and sequencing the genome. By designing studies at a national scale, such as SG100K important findings will emerge that can shape the future of medicine and public health. It is this type of strategic approach to national projects, broad collaborations between research projects and institutions and the investment in science and technology that positions Singapore for success.

You have been instrumental in initiating the Qatar Genome Project and, recently, the Qatar Precision Medicine Institute. What is unique about Singapore’s program in Precision Medicine?

Singapore’s unique strength in population genomics research is that it is a multicultural country with three major ethnicities that are understudied. The data would be representative of the diversity in Singapore and the wider Asian population. With the data generated from PRECISE, other countries in Asia can validate their local findings and discover additional genomic markers. Singapore could become a hub for genomics and precision health research in Asia.