Can GalNAc conjugated oligonucleotides still be improved?

In this exclusive interview we spoke to Marie Wikström Lindholm, PhD, VP, Head of Technology Innovation at Silence Therapeutics, about how GalNAc conjugates can still be improved and the biggest challenges that still need to be overcome. 

Some would say there isn’t anything left to investigate with GalNAc conjugates – I assume you don’t agree?

'It has been very clear at meetings over the last couple of years that everyone has confirmed GalNAc conjugated oligos really work and have basically revolutionized our industry. So, now, I frequently meet people who ask 'why are you working with the GalNAcs, is there anything left to do?'

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In-house at Silence...we think there is still plenty of room for improvement. Because of that, and because this is something I feel quite strongly about, it's actually been a pleasure to see based on today's talks that quietly everyone else in the industry seems to be thinking the same thing. We have something that works, but it doesn't meant that we can't make it better.'

Where do you see the biggest areas of potential?

'If you look at the data on the injected dose - because these compounds have to be injected subcutaneously - first of all, we lose about 80% of it within the first 24 hours through urine, and secondly, it is actually just a tiny fraction of the remaining compound that reaches the final destination.

So this is one of the things where we really do have room for improvement. Our compounds are very expensive and will continue to be very expensive so if you can increase the amount that actually reaches the final destination, by just a factor of 10, that would be a huge advancement because it would make it possible to reduce the dose. There really is plenty of room for improvement here.'

What are the biggest challenges that still need to be overcome?

'I could talk about this for a full day, but I think it all boils down to the fact that we know that just a tiny fraction reaches the final destination. In order to get to the right point, it needs to do an endosome escape and that sounds easy, but it has been a burial ground for so many methods in the past because we want it to get into the cell through a pathway that the cell has evolved a defence against over millions of years. Basically we want to do the same thing - getting foreign genetic material into the cell - that cells have evolved protection agents against because that's the way that we get infected by a virus or bacteria.

What's next for us is to try and do something about this in our own way. So we have been working under the banner 'less is more'; we have quite complicated molecules - all of us do - we have certain modification patterns, we have what's called a GalNAc tri-cluster and we have in a systematic manner been looking at that delivery method to see how much of it is really necessary and how much we can simplify the molecules. By doing so we have made some interesting discoveries where we saw that not only could we simplify the molecules and keep activity, but we were actually able to improve it.

We do think that GalNAc conjugated oligos can get better and we also think that some of the basic structural features that we are now using in the new and improved GalNAc conjugates could be used for other targeting as well.'

This interview was filmed at TIDES Europe in November 2018.

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