Hulskof schreef op 30 september 2021 10:21:
Goeie twitterreeks van Ali Mortazavi (CEO van X-therapeutics, ex-CEO van Silence)
A thread on #GeneEditing and #rnai . Just my thoughts but very happy to be corrected by others:
1/ The data from @BeamTx, @intelliatweets @VerveTx are truly exceptional and great achievements. ??????. That said, there are a few limitations…
2/ The main issue is that the best data is in the liver where unluckily (luckily for $etx), they are up against the truly remarkable properties of GalNAc + siRNA delivery/silencing system…
3/ This platform allows for long duration of silencing (up to 6 months), in effect the same targets as #GeneEditing, with a SubQ injection and the benefits of RNA transiency. Currently, given all the variables, I don’t see why anyone would edit rather than use #rnai
4/ That said, there are great opportunities for #GeneEditing outside of the liver. The same rate limiting factor of delivery systems for #rnai is the issue with a BIG difference: #GeneEditing should only require one shot of an LNP for example.
5/ So, if #GeneEditing companies can target any other cell type than hepatocytes, they will have a significant opportunity. Sadly, nothing like GalNAc exists for other cell types. Any #rnai approach would need repeat dosing, steroids, etc which would be a big disadvantage…
6/ There is a lot of excitement and work going into LNPs by #GeneEditing companies to achieve this. But they face some major hurdles: If you’re going to be editing, your delivery system needs to be very cell type specific. Any distribution to other cell types, edits those genes
7/ Having worked for years with LNPs, I’ve yet to see anything which is cell type specific enough. Even LNP to the liver leaks. It’s very good but there’s some leakage. This is acceptable leakage but the liver is a special organ and consumes everything ??
t.co/XHyN5p43sD8/ The other big issue is, even if you achieve cell type specificity, you only get one shot at it. You then need to cover every cell and edit very efficiently. Partial editing is not good. Lastly, even if you get ‘perfect’ editing, is that a good thing?
9/ In the example of TTR, it’s questionable if maximum inhibition is beneficial, if not harmful. Some TTR expression is needed, no one knows how much. Levels of gene expression are a very important consideration. So in conclusion…
10/ Everyone has the same problem. There’s too much focus on the cargo (siRNA, editors, etc) when the rate limiting factor is cell type specific delivery systems. Good luck to everyone, people taking medicines don’t care what’s in them. They just want to feel better.