10000%

If this is correct, it’s insane for the FDA to change its mind after the trial was already run to their desired design .

We speculate that this is due to lowering of HTT1a, a specific form of HTT mRNA that arises from a failure of exon-1 to splice to exon-2, leading to alternate cleavage and polyadenylation that was discovered and characterized by Gill Bates's lab at UCL.

So, we can say that targeting intron-1 with an ASO in this case leads to really striking rescue of molecular features of HD in a knock-in mouse...

Changing transcripts could be good or bad, but if we look at HD people's favorite genes, we see a very striking pattern of rescue when we target intron-1 with an ASO that we don't see if we target downstream:

Surprisingly, this is the first mouse HTT ASO experiment to show robust transcriptional rescue. If we look at just the mutant mice by bulk RNASeq, a more distal HTT ASO (left) changes exactly two transcripts - one of which is HTT itself. But targeting intron-1 leads to a huge change of transcripts:

The ASO targeting intron-1 basically eliminates aggregates while the more downstream one does nothing:

This is pretty niche!

5. Wars are easy to start and hard to stop

Wow, congrats!

Being in the military is an interesting experience of what it means to be really filthy, which is kinda what I figure they’d look like?