Dr Mitchel Tate : using gene therapy to improve diabetic cardiomyopathy

Wednesday, 14 Mar 2018

Challenge: can you describe the aim of this project in 10 words?

To improve diabetic cardiomyopathy using cardiac-targeted gene therapy.

Why gene therapy for cardiomyopathy?

There are several advantages of using a gene therapy over a traditional pharmacological approach. Firstly, gene therapy can be organ targeted, or even cell-type targeted (e.g. to the cardiomyocyte), meaning it is possible to avoid stimulating (or inhibiting) your target in other organs, which may elicit a detrimental effect. Gene therapy is also long lived, potentially lasting up to several years in human patients, which may be an advantage over other medications. At present, the current cost of these therapies is somewhat restrictive, however, it is hoped that continued R&D will lead to a significant reduction in price, leading to adoption in the clinic.

What have you already discovered about potential targets?

Diabetic cardiomyopathy is a complex disease characterised initially by myocardial fibrosis and diastolic dysfunction, and leading eventually to clinical heart failure. Many pathophysiological mechanisms including impaired cardiac insulin signaling, mitochondrial dysfunction, oxidative stress, inflammation, calcium handling have been implicated (and reviewed here), however their relative contribution to overall disease pathogenesis remains unknown and may well differ case-to-case. This complexity means a “one size fits all” approach is unlikely to work, and as such our laboratory is pursuing several strategies (both gene and drug). I have recently identified – here and here – several targets of myocardial fibrosis and cardiomyocyte hypertrophy that show particular promise, improving cardiac function in diabetic mouse models.

What aspect of this current research excites you the most?

Recent progress taking cardiac-targeted gene therapy into clinical trials in heart failure patients (however, not specifically in diabetics yet) is making this area of research very exciting. These clinical studies have highlighted several pitfalls, which can, and need to be untangled, but most importantly have highlighted the promise of using this approach.

How long before this work might impact clinical care?

Although my experiments are designed primarily to be proof-of-principle identifying potential targets to be exploited in treatment, the use of gene therapy is gaining some traction in the clinic. In future, we hope to be in a position to take a more translational approach, and if so, our laboratory is very well positioned given previous success in the drug discovery and commercialisation of projects.

What’s your research Holy Grail – the one thing you’d like to achieve in your career?

Apart from the obvious – to develop a novel therapy that will delay the progression of diabetic cardiomyopathy in people with diabetes – I would like to better understand the process of diabetes-induced heart failure. Our current lack of knowledge surrounding disease pathogenesis, the inability of routine screening techniques to detect diabetic cardiomyopathy in its early stages, and the long-term asymptomatic nature of the disease, means patients are only identified once heart failure is evident, and this is often too late to intervene effectively. If I was able to contribute to disease understanding and influence clinical management, either in terms of screening or treatment, and subsequently have a positive impact on people’s lives and well-being, that would be very satisfying.

What is your biggest research hurdle?

Trying to establish a career as a researcher when everybody around you is also doing great work, is particularly difficult; if only there were enough resources to go around! As a non-Australian committed to research and as an active participant in Early Career Scientist initiatives, the restriction on non-Australian citizens/permanent residents to apply for [most] early career fellowships is an on-going source of frustration, especially as the early career stage is a crucial phase of a researcher’s career. Having said that, after migrating from the UK, I’ve enjoyed two very productive years working at the Baker Heart and Diabetes Institute in Melbourne, exposed to world-class facilities and fellow researchers across Melbourne and Australia, all eager to collaborate at every opportunity.

Who has inspired you in work or life?

I have been spoilt by having a series of mentors/supervisors who have guided me along my journey from England, Spain and Northern Ireland to my current position in Melbourne. The most influential person to date is definitely my current supervisor at the Baker, Professor Rebecca Ritchie, who has a habit of pushing me beyond my comfort zone in order to pursue every opportunity available to me.

If you could only keep three possessions, what would they be?

I’d probably keep three pairs of running shoes as they don’t last very long and I like to run!

Can you nominate a book that influenced you?

Reading Nature via Nurture: Genes, Experience and What Makes Us Human by Matt Ridley before university really piqued by interest in complex diseases such as diabetes, and the importance of the interactions between the environment and genetics.

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