SYNGAP1

So, so there are, there are specific gene sequences that tend to be heavily correlated with it.

So SynGAP1 is one of them.

So SynGAP1 is a mutation that, you know, codes protein sheathing for your neurons, and so typically SynGAP1 is associated with profound autism.

It isn't profound autism.

It doesn't always cause profound autism, and there are a range of functions for people who have SynGAP1.

But SynGAP1 is just, like, one example of, of something that tends to heavily correlate with autism.

There are many people who have profound autism who don't have the SynGAP1 mutation.

And so what we mean by spectrum is essentially a broad range of behavioral clusters, and what we have now is sort of a broad range of behavioral clusters of behavioral clusters.

Hello, Syngap land.

My name is Mike Corralia.

This is episode 217 of the Cure Syngap1 podcast, and I'm only going to talk about ASOs today.

Believe it or not, this is my fifth attempt at recording this episode because I have way too much content to get through.

So I am going to really move quickly and point you to show notes because all of these thoughts go together, but cramming them into 10 minutes is just going to be tricky.

That's the point I'm trying to make here.

But I do wanna really talk about the Angelman study because there's a lot to learn from this.

And Angelman and Syngap are incredibly similar.

Yeah, we initially had done some work in a liver target called CPS1 for urea cycle disorder, but we really felt that wasn't exactly a haploinsufficiency, but we were generating some data in some CNS groups.

indications with very clear haploid-sufficient mutations, and SYNGAP1 was part of this.

And we really were excited about the data, and it really was amenable essentially to the effect on transcription that we're having so maybe just to point this out right we're not getting five tenfold increases in expression we're getting like we're getting like twofold right so that that might be a bit of a limitation but it's also really it points us to which therapeutic areas could be beneficial with our with our or fit our platform in terms of like where a modest increase could have you know pretty thing that could have a pretty significant benefit But it's also nice that from a safety perspective, I think there could be concern about increasing the expression of a gene tenfold.

I don't think from a safety kind of talks and development perspective, that's not great either.

Sometimes you'll have missense mutations or amino acid substitutions where you have full loss of function or the protein is no longer stable.

So by targeting the regulatory RNAs, we are increasing both, but you're essentially increasing the healthy one and then you're increasing one that's basically just being degraded anyway.

So that's really, for example, in SYNGAP1-related disorder, about 80% or so of patients have either nonsense or franchise mutations where they have a mutation, premature stop codon, that RNA is just being degraded.

They're never even making SYNGAP protein from that dysfunctional allele.