NLRP3

Next, Dr. David Salmon from Moffitt Cancer Center discussed findings and implications from a Phase IIa study assessing Ophirnoflast in lower-risk MDS.

Given that Ophirnoflast acts upstream as a first-in-class NUK7 and NLRP3 inflammasome inhibitor, how compelling are the biomarker data in proving true disease modification rather than just symptomatic erythroidous support?

Yeah, so I think the data supporting the concept is now over 10 years ago.

A really seminal publication was back in 2016 that kind of shows this pathway is central to sort of all subtypes of MDS, not just a specific one.

what's so exciting.

Right, which is called the NLRP3 inflammasome pathway that we discussed earlier.

So Dapsone had this dual effect of lowering inflammation in the brain independent of whether you have Lyme or not.

And that's why the drug really needs to be looked at and repurposed.

Because in a Korean study of over 4,000 people with leprosy, where they gave rifampin and dapsone for years, what they found is The ones who took Dapsone for 15 years, their Alzheimer's rates were six times lower than the people that never took Dapsone.

And we don't know whether that population actually had Lyme or whether the Dapsone was just affecting this NLRP3 inflammasome pathway, lowering neuroinflammation in the brain.

But the point is, this opens up a whole new area of research, considering that we are in the middle of an Alzheimer's epidemic, just like we're in the middle of a Lyme epidemic.

And now I think You know, there's a reason why the Lyme epidemic may be affecting the Alzheimer's epidemic is because I discovered that all 16 M-synch factors are associated, but also that Borrelia burgdorferi is going to be one of the co-factors.

And it's for what N L R P three stands for is not like, so N O D like receptor family pyrin domain containing three.

I'm not even going to keep on with that, okay? But the biology of this is quite interesting because that molecule NLRP3 activates and it causes, it has two stages.

One is priming and one is activation.

And think of the priming as it's getting the system ready and then the activation is, oh, something dangerous has actually happened.

So the signaling is, that this NLRP3 causes, right? The signal one, which is priming, the inflammatory receptors can activate signaling pathways, including NF-beta, okay? And that can increase the production of components like pro-IL-1-beta or pro-IL-18.

And the inflammasome-related machinery The cell is loading this ammunition and then the signal for activation comes in.

And so with activation of this involves multiple danger associated events such as reactive oxygen species, potassium influx, mitochondrial dysfunction, cellular stress.

And, and in this arena in early biotech and startup world, it's very rarely the first idea, the first target, um, that you bu- that you have in your initial vision that pans out.

Um, you know, we've been very fortunate, uh, to date in that NLRP3 and SARM1 specifically for 10b were our top two priority programs when we launched the company.

And we were able to deliver on advancing assets for both into the clinic within a two-year timeframe.

I think that's not very common.

These will stimulate a pathway called Nrf2.

The third pathway is called NLRP3 inflammasomes.

Now, this is important in cancer, in Alzheimer's disease, in most chronic illnesses that you're going to see.

How do you shut it down? Well, it turns out these first two things we talked about, NF-kappa-B, Nrf2, if you take these supplements with curcumin, broccoli seed extract, resveratrol, by the way, is also a great Nrf2 stimulator, hits the sirtuin genes of the body for longevity, right? It's part of my protocol.

It also affects NLRP3 inflammasomes, but you also do it with low-dose naltrexone and low-dose melatonin.

Wow.

Taken at night, before bed?

Yeah, and if you have a problem sleeping with LDN, I take actually mine in the morning just to make sure it's not, but I take 4.5 milligrams of low-dose naltrexone compounded through Infuserv in Florida.

When those crystals, uh, solidify, because the dielectric constant of water decreases, an inflammasome is triggered.

That inflammasome pathway is the NLRP3 pathway, and this causes, you know, a unified disease, uh, pathway in diabetes.

Okay? This is-- explains why diabetics often get gout.

And then you gotta ask the next question that's present in centralized and functional medicine, because you know the functional medicine guys always try to tell you that, that insulin resistance is a big deal, and you know that centralized medicine, especially in Type 1 diabetics, often uses insulin.

Um, but it also, it causes a systemic inflammation.

There's a specific, uh, enzymes called NLRP3 inflammasome.

So, um, what it does is it increases the inflammation.

We call it systemic inflam- inflammation, and, uh, it also causes oxidative stress.

... biology.

And so usually those people that are more over-trained, you get more of that NLRP3 inflammasome, and that just drives so much more systemic inflammation.

So those people get it, and they're hyper-responders 'cause you're cleaning out everything from the system that you've accumulated.

So it makes sense that he got such a robust response.