Tau protein

One of them is tau.

It's the MAPT gene that creates tau.

And that's one group.

That's the group that's the vanishing families part of.

Right.

Chronic traumatic encephalopathy, otherwise known as CTE, is characterized by a pathognomonic lesion consisting of a perivascular accumulation of neuronal phosphorylated tau protein, variably alongside astrocytic.

I can keep going on this, but I don't think that's what we want.

I don't think it's particularly useful.

In the brain, I think I lost mine.

That was good, Phil.

In the brain, there's a protein called tau, T-A-U.

And tau normally does a structural job.

So that's that one.

Next T is the tau protein.

So tau protein is something that's just kind of gaining some more talk within the concussion world.

I say more because it's been around for a little bit, just kind of buzzing.

But there's a bunch of recent studies that identified this tau protein as a fluid biomarker of concussion and other neurodegenerative diseases.

But in general, after a concussion, those tau protein raise, the levels raise in both the blood and CSF, our cerebrospinal fluid, due to the damage to the axons and the microtubules on the brain.

So because of the damage, those tau proteins can detach.

They can do something called misfolding and then leak into the blood and to the CSF, which is why we see the rise when we do this test.

And we offer it at Function Health.

We also offer a PTAU testing, which is a biomarker that actually looks at progression and brain degeneration around Alzheimer's.

And it's kind of like a cholesterol test.

You can modify it by

So familial FTD, our, our mutation of that, I think there's three most common ones.

Ours is MAPT or MAPT.

Yeah.

So that means that our, our mum carries the faulty version of that gene, and our dad carries the working version of that gene.

The anti-interferon gamma antibody may prevent the induction of tetherin, an important cell autonomous antiviral pathway that interferes with egress of virus from the plasma membrane.

Thus, in the presence of the anti-interferon gamma, herpes virus may be able to leave the neurons despite the pTau.

Okay, so we had some question about what these anti-- And so Carol has a suggestion, but I cannot put it in context now because I forgot everything.

I, my-- 'cause I probably have phosphorylated tau.

That's just one example of many of our push to bring RNAi outside the liver and to where disease is.

Yeah, and just to kind of fill out the context on that, that was the MAPT program that uses a brain shuttle to deliver the sRNA into the brain and to try and get sort of more even sort of biodistribution in the brain as compared to an intrathecal approach, correct?

Yes, and I apologize.

You probably were planning on talking about that later, and I'm throwing you – That's

Yeah.

And just maybe just a review for our listeners, just, you know, the strides you have made with regard to delivery.

So we already mentioned, obviously, the news yesterday about the MAPT data, which gets, you know, as you say, sort of establishes the opportunity for a platform approach to CNS delivery or into the brain.

You've already shown clinical data in delivery to adipose tissue for a program that we'll touch on here in a bit.

Interim data from an active Phase 1-2a trial of AeroMapti, the Arrowhead Pharmaceuticals RNAi-based therapeutic candidate targeting tau accumulation in Alzheimer's disease and related tuopathies, have returned favourable results across the measures assessed so far.

Among healthy participants, subcutaneous administration of ARO-MAPT produced sustained decreases in total tau protein levels measured in cerebrospinal fluid, averaging as much as 73% by day 105 and reaching a peak of 85% in individual cases.

The company says those findings point toward the feasibility of dosing once every three months.

Tau protein accumulation beyond normal levels has been linked to conditions including Alzheimer's disease, MAPT-related frontotemporal dementia and progressive sopronuclear palsy.

ARO-MAPT targets the MAPT gene within the central nervous system, reducing that gene's activity until output across all six tau protein isoforms falls.

The ARO-MAPT SC1001 study is a placebo-controlled, dose-escalating trial enrolling approximately 64 healthy participants alongside as many as 48 individuals diagnosed with early-stage Alzheimer's disease.

It is assessing Aromapt's safety profile, tolerability, pharmacokinetics, and biological activity.

By day 105, doses of 2.1 milligrams per kilogram and 6.4 milligrams per kilogram each delivered across three administrations on days 1, 8, and 15 produced average tau reductions of 40% and 69%, respectively.

And they know exactly what it is.

It's a mutation on the MAPT gene that creates the tau protein.

And I said to them, I said to Barb in that first call, "Do you mean to tell me you can look at a slide or at a image on a computer and say, 'Yes, that's my disease?'" And she said, "Yes." And I said, "But I thought we were in the era of gene editing.

I thought that this was the CRISPR age.

But again, frontotemporal dementia is a word the same way that cancer is a word.

There are a lot of different cancers, and there are a lot of different FTDs.

And so the FTD this family has involves a gene called MAPT, but some people with FTD, it involves a gene called progranulin and another one C9orf72.

And then, of course, there are other dementias that are classified as FTD that, like cortical basal degeneration, which your friend had.