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ESC Paul Hugenholtz Lecture for Innovation: Dr. John Maraganore

Silencing the messenger: RNAi therapeutics as a new class of innovative medicines

29 Aug 2021

This year’s presenter of the ESC Paul Hugenholtz Lecture for Innovation is Doctor John Maraganore, Chief Executive Officer and a Director of Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA. His development of RNA interference (RNAi) therapeutics – drugs that simulate the natural biological process of interfering with mRNA to regulate gene expression – is helping to open up a whole new avenue of medicine.


What got you interested in drug development?

I entered the biotech industry in 1984 after completing my PhD in biochemistry. At that time, there were remarkable opportunities for investigating the use of recombinant DNA technology to shape novel biologic-based approaches for the treatment of disease. I was so motivated by the possibilities that, over 35 years later, I find myself in the same industry, as committed as ever to the advancement of innovation for better medicines.

Early in my career, I was the inventor of bivalirudin and was able to take the drug all the way to regulatory approval. This early success whetted my appetite. When I joined Alnylam Pharmaceuticals in 2002, I was already interested in the incredible potential of RNAi therapeutics and wanted to explore them further.


Tell us something about your lecture topic

The main focus of my lecture is the technical challenges that need to be addressed to allow RNAi therapeutics to progress to approval by regulatory authorities. The lecture spans opportunities in two areas: one is the advancement of several programmes for the treatment of rare diseases, and, on the other side of the coin, I discuss the development of RNAi therapeutics in more prevalent diseases. Relevant to the latter, my lecture mentions promising results that have been achieved with inclisiran, now approved in Europe for the management of hypercholesterolaemia.


What do you see as the main challenge in developing innovative medicines such as RNAi therapeutics?

There is no doubt that there is a huge amount of innovation emerging from industrial and academic science right now, with enormous implications for the treatment of human diseases. I think that the biggest challenge is how societies will pay for this innovation and how they will incorporate the cost into the fabric of their economies. But I am very optimistic that solutions will be found because the alternative for countries – that is, to continue to pay for the consequences of untreated common diseases, including cardiovascular disease – is much, much more costly.


Looking ahead to the future, what are you most excited about?

I am interested in a whole range of technologies and am optimistic about the future for many innovative approaches, including gene therapy and cell therapies. However, my passion is for RNA-based medicines, and I am particularly excited about the enormous opportunities available in this area, including the ability to achieve delivery of RNAi therapeutics to a broader range of tissues to allow the treatment of even more diseases.

One particular area where RNAi therapeutics could make a tremendous difference is in hypertension, where a big issue is poor patient compliance. By using a treatment that only needs to be given once every three or six months, we are exploring the possibility that we can reimagine the treatment of hypertension and lessen the impact of this leading cause of morbidity and mortality.

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