An FDA-approved anti-HIV drug, given orally at a microdose, extended survival in mice carrying human prion protein and infected with human sporadic Creutzfeldt-Jakob disease prions. Efavirenz works by activating CYP46A1, the brain enzyme that converts cholesterol into a form that can leave the brain, rather than by lowering the prion protein itself.
0:00Welcome to Base by Base, the paper cast that brings genomics to you wherever you are. Thanks for listening, and don't forget to follow and rate us in your podcast app. This is the 4th article in our series on Kreutzfelt Jockup Disease, a series that began in August 2026 as a dedication to Lido Sousa, the Brazilian Aviation communicator who made his diagnosis public.
0:20Every episode so far has followed one idea, lower the prion protein. Silence the gene, cut the RNA, starve the disease of the raw material it needs. Today we leave that road entirely. Today's drug does not touch the prion protein or its RNA at all, and it is already sitting in pharmacies around the world.
0:39Yeah, it's, um, it's honestly one of the wildest things in pharmacology when this happens. Right. I mean, imagine walking into a pharmacy today, grabbing a standard generic HIV pill, something that was 1st approved back in what, 1998?
0:52Yep, late 90s. Right. And discovering that this exact pill might hold the key to fighting a 100% fatal brain disease and not because of what the drug was actually engineered to do? No, not at all. a complete biological accident.
1:03Exactly. You run these massive clinical trials for a viral infection. 1000000s of people take the drugs safely for decades, and the whole time it just, it's doing something else in the background. An off target effect.
1:15Yeah, a totally unintended off target effect that nobody designed, which turns out to be exactly what you might need for a radically devastating brain condition. It really is the ultimate plot twist in drug discovery.
1:26We spend, you know, 1000000000s engineering these molecules to hit specific targets, but the reality is pharmacology is still full of these surprises. It makes you wonder what else is just sitting on the shelf, right?
1:38Exactly. It forces you to step back and realize how much untapped potential might be hiding right in front of us. So, if you've been listening to our earlier deep dives on sporadic Kreutzfeldt, Jacob disease or SCJD.
1:52You know, we've been pretty laser focused on one main strategy. Yeah, the PRP lowering approach. Right. We explored divolent Cirin A. We unpacked anti-sense alliga nucleotides, different tools, obviously, but they all share the exact same mission, which is to lower the cellular pryon protein.
2:08Because up until now, the logic in the field has been um, incredibly singular. Prion diseases happen because a normal protein, PRPC, misfolds into a toxic form. PRPSC. Right. So the prevailing thought has always been, if you just remove the normal protein, you remove the fuel, starve the fire.
2:28But the research we are diving into today is a massive pivot. We are looking at a drug called a favorance, and this drug, it does not bind to the preyon protein. It ignores the protein's RNA completely.
2:40What it does instead is, well, it alters how the brain handles cholesterol. Which is huge. Having this 2nd completely mechanistically independent route is monumental for the field. Because we need a backup plan.
2:53Exactly. We are talking about a rapidly fatal neurodegenerative disease. There is no cure. There are no disease modifying treatments available right now. If the PRP lowering strategies. happen to hit a wall in clinical trial.
3:06Which happens all the time in neurology. All the time. Maybe due to unforeseen toxicities or maybe they just can't penetrate deep enough into the brain tissue. If that happens, the field is not back at square zero.
3:17We have this parallel completely distinct strategy. And we really need to point out the practical reality of this without overselling it, of course. But the PRP lowering drugs from our previous deep dives, they require intense delivery methods.
3:30Yeah, you're talking about administration directly into the spinal fluid. Or the brains, ventricles, yeah. But if favorance. It's a pill. You literally take it by mouth. The logistical contrast is night and day.
3:42A daily oral pill completely changes how a treatment could be deployed, especially for a patient who is already dealing with severe neurological decline. So, who actually figured this out? We have to give major credit to the brilliant team behind this paper.
3:55Yeah, the Calgary group. Right, right. The Calgary Prion Research Unit, the Hotchkiss Brain Institute, and the Snyder Institute at the University of Calgary. The work was led by Seabeam Gilch, and Hermann Schatzel, alongside 1st author Tahir Ali, Jessica Kashin, Hana Ahmed Hassan, and their colleagues.
4:12And it wasn't just the lucky guess, right? They were building on their own stuff. Exactly. This builds directly on our foundational work. A while back, this exact team discovered that E-Faverins actually worked against mouse adapted scraby pryons in infected mice.
4:28But to really understand how they made the leap from that early mass scrapy discovery to this new paper, we have to talk about the brain and its cholesterol, because it's wild to think about the brain having its own, like, isolated cholesterol ecosystem.
4:43It really is. I mean, the brain makes up about 2% of your body weight. But it holds roughly 20% of your body's total cholesterol. Wow, 20%. Yeah, it's a massive hoard. And because of the blood brain barrier.
4:55It can't just pull what it needs from your bloodstream. It has to manufacture its own supply from scratch. It's like a walled garden. Exactly. It uses that cholesterol for vital functions, you know, building cell membranes, insulating nerve fibers, forming synapses.
5:10But just like any factory, if you overproduce, you need a waste management system. Because it can't just dump the bulky cholesterol back across the barrier. Right. And that's where a highly specific enzyme comes in called CYP 46 A1.
5:23CYP 46 A1. Got it. Think of it as the brain's cholesterol exhaust pipe. Normal cholesterol is too big to cross back over the blood brain barrier. So this enzyme chemically converts the excess cholesterol into a specialized molecule 24s hydroxycholesterol, or just 24 SHC.
5:42And that smaller molecule can get out. Yep. Once it's converted to 24 SHC, it easily slips through the barrier, enters the bloodstream, and gets carried away to the liver for disposal. Which brings us back to the accident with the favrins.
5:55This HIV drug happens to interact with this exact exhaust pipe. At a very specific microdose, yes. It functions as an allosteric activator of CYP 46A1. Let's demystify that term real quick. Allisteric activator.
6:07Right. So being an allosteric activator means efavrins doesn't just step on the gas pedal, it is more like finding a secondary keyhole on an engine block. When the drug docks into this specific spot, it actually changes the physical shape of the enzyme, making it work faster and more efficiently.
6:21It opens the exhaust pipe wider. Exactly. And the team's earlier works show that nudging this exhaust pipe open managed to clear mouse scrapy dryons. But that sets up a massive hurdle, like a really depressing hurdle in this field.
6:35Because compounds that work beautifully against mouse scrapy. They almost universally fail when they are tested against actual human pryons. It's the heartbreak of prion research, honestly. Let me push back on this for a 2nd for the listener who might be wondering.
6:48If a drug cures a mouse of scrapy. Why on earth does it fail when we try it on a human with sporadic CJD? Like a misfolded pryon is a misfolded pryon. That is the assumption that has broken a lot of hearts.
7:01Yeah. But you cannot just copy paste a scrapy result onto human CJD because a pry on strain diversity. Screen diversity. Right. Think of the normal prion protein, like a flat piece of paper. A pryon infection is like origami gone horribly wrong.
7:15Okay, I like that visual. But it doesn't just fold one way. The mouse adapted scrapey strain, might fold the paper into, say, a jagged throwing star, but the human CGD strain. It folds it into a complicated swan.
7:28Ah, so a drug might be perfectly designed to lock onto a structural crease in the throwing star. But that crease simply does not exist on the swan. Right. The scrapy strain used in most labs has vastly different biochemical shapes, incubation times and pathological properties than human SCJD.
7:46So scrapy result is an exciting clue, but it is absolutely not proof that you have a drug for human CJD. Okay, so if curing scrapy doesn't prove anything for humans, How did this Calgary team actually prove they had something real here?
8:00They use a brilliant, highly specialized humanized mouse model called TG650. Okay, so these mice are genetically engineered to overexpress the human prion protein, specifically the 129 MM variant. Oh, exactly, which is the exact genetic backdrop, most relevant to human sporadic CGD.
8:17But the real kicker is what they infected them with. They didn't use mouse scrapy this time. Yeah, they didn't. They infected these mice with prions taken directly from an actual human sporadic CJD patient, the MM1 strain.
8:28By combining the human protein backdrop with the actual human pathogen. They created the ultimate testing ground that their earlier work just couldn't provide. And they gave the favrins orally, just mixed into the mice's drinking water.
8:41But we need to make the dosing explicitly clear here because it is probably the most critical detail in the entire paper. It really is. They gave roughly 0.09 milligrams per kilogram per day. I want to repeat that so it's unmistakable.
8:550.09 milligrams per kilogram per day. This is approximately 300 to 400 times lower than the standard dose given to patients with HIV. It is so important to emphasize that. We are not saying, you know, give a person with CJD and HIV pill.
9:09Right, because a standard antiviral dose would be massively too high. It would introduce unnecessary side effects. Toxicity? This is a deliberate extreme microdose. The researchers aren't trying to fight a virus.
9:22They're just trying to gently nudge that one single enzyme, CYP 46 A1 into a higher gear. So to see if this microdose actually mattered. The researchers set up 2 distinct treatment timelines, an early treatment group starting 30 days after the mice were infected, and a late treatment group, starting 130 days after infection.
9:40And we have to focus on that late arm, because clinically, it is the only one that reflects reality. Right, because people don't know they have CJD on day one. Exactly. Human patients go through a long, silent incubation period.
9:53They only show up at the neurologist's office after severe symptoms begin. If a drug only works when given 10 minutes after exposure. It's basically useless in a real world clinic. Totally. So let's look at the survival results because the numbers are fascinating.
10:08In the untreated mice. The disease just ran its brutal course. They showed early clinical signs like a rigid tail, hunched posture, rough coat around 165 days. But in the early treatment group, the 30 day group, their survival was extended by an average of 17 days.
10:26Which is great, but the late stage group, the ones that didn't receive a single drop of the drug until 130 days into the infection. They saw their survival extended by a mean of 23 days compared to the untreated mice.
10:37A 23 day extension, from a late stage treatment. But for a listener trying to gauge this. I mean, in a rapidly fatal disease model like this, how significant is 23 days, really? It is a profound effect size.
10:51The researchers calculated something called Cohen ASD values to measure the true magnitude of this. In standard statistics, a Cohen's D of 0.8 is considered a very large noticeable effect. Okay, .8 is large.
11:05The value for this late treatment group was over 3.0. Oh, wow, over 3.0. Yeah. In the context of a notoriously aggressive, fast moving disease that usually kills within weeks of severe symptom onset, buying that much extra time is massive.
11:20But they found a really critical nuance when they actually look inside the brains, didn't they? Because they didn't just wait for the end of the disease, they analyze the brains at the early clinical stage around day 176.
11:31Right. And when they checked it 176 days, the treated mice had a significantly lower accumulation of PR plus C, the toxicness folded prions. So the drug was actively holding the disease back. Keeping the pryon loads suppressed, yes, but... But when they looked at the brains at the terminal stage, when the mice eventually succumbed, the pryon levels looked pretty much the same as the untreated mice.
11:52Yeah, the accumulation eventually catches up. It's sort of like, think of the brain's cholesterol clearing system, like a sink drain. The efavorance opens the drain wider. It clears out the material and keeps the water level down for a long time.
12:04Buying you weeks of extra survival. Right. But eventually, the prime replication is like a faucet turned on full blast. Ultimately, the sink overflows anyway. That's a great way to visualize it. But it does beg the question, what is the actual connection between the drain and the faucet?
12:22Like, how does clearing out cholesterol stop a protein from misfolding? Yeah, let's get under the hood here. It comes down to where the misfolding happens. Bryons need a very specific environment to do their work.
12:33They anchor themselves to the outer surface of the brain cells, specifically in areas called lipid rafts. Lipid rats. Think of lipid rafts as specialized cholesterol heavy docking stations on the cell membrane.
12:45The prions require these docking stations to efficiently convert the normal protein into the toxic form. Okay, but how does the brain get so flooded with cholesterol during an infection in the 1st place?
12:55Does the prion just passively use what's already there? No, it's more sinister than that. The Prion actively hijacks the system. The infection triggers a cellular panic response. It activates a transcription factor called SREBF2.
13:08S-R-E-B-F2. Basically, SREBF2 is a biological hoarder. It tells the brain cells to ramp up cholesterol production and refuse to throw any of it away. Yeah, so the cells start packing all this excess cholesterol into storage units inside the cell, known as lipid droplets.
13:25And this paper maps out exactly how a favrince breaks that cycle, right? Exactly. The researchers prove that treating the mice with the favrins prevents the activation of SREBF2. They verified this by looking at parallel up in two.
13:37Which is a marker. Right, paralipin 2 is just a protein marker that coats the outside of those lipid droplet storage units. If favrins drastically reduced parallelip in 2 levels, meaning fewer storage units, and less hoarded cholesterol for the prions to exploit.
13:51And they even want to step further to make it visual. They use something called fillipin staining. Oh, yeah, the standing is fascinating. It's a specialized fluorescent dye that literally makes free cholesterol glow under a microscope.
14:03And when they looked at the treated brains, the intense glowing buildup of cholesterol was drastically reduced. And they proved, these storage units were clustering right in the neuronal environment where the pryans do the most damage.
14:16Okay, wait, let me play devil's advocate here. If this pill moves into human trials, how do we know it's actually working in a living patient's brain? I mean, if I give a patient a drug that alters cholesterol, and I take a blood test, couldn't an elevated cholesterol reading just mean the drug is messing with their liver, you can't exactly take a biopsy of a living person's brain to check their lipid droplets?
14:37That is an excellent point, and it's exactly why the 24 SHC metabolite is the hero here. Remember how we said CYP 46 A1 converts the bulky brain cholesterol into 24 SHUC so it can exit the exhaust pipe?
14:51Right, the smaller molecule. Well, 24 SHDs is produced almost exclusively in the brain. It is this specific signature of brain cholesterol turnover. So when it leaves the brain and enters the peripheral bloodstream, it acts as a perfect, highly specific biomarker.
15:07Oh, that's incredibly convenient. It really is. The researchers found elevated levels of 24 SHC, not just in the brains of the treated mice, but in their blood serum. Meaning a simple blood draw could tell a doctor if the microdose is successfully engaging the target enzyme inside the brain without getting confused by liver cholesterol.
15:24Exactly. It gives clinicians a non-invasive window straight into the brain's libid metabolism. And, you know, the researchers wanted to leave absolutely no room for doubt about this mechanism. So they took it to the Petri dish.
15:35They did. They ran an invitro experiment using N2A cells, basically, mural brain cells grown in a dish. They infected them with prions, and then they genetically forced them to pump out extra of that CYP 46 A1 exhaust enzyme.
15:50Without even using beef of Erin's drug at all. Exactly. Just the enzyme itself. And they saw the exact same result. The pryons were reduced and the 24SHC exhaust went up. Which proves definitively that the enzyme activation is what's slowing the disease.
16:05The drug is literally just the key that turns the engine. Exactly. Now, I have to ask about older drugs. Because we've had cholesterol lowering drugs for decades, right? Statins like lovestat in our school statin.
16:15Why is this microdosed HIV drugs superior to just, I don't know, aggressively starving the brain of cholesterol using the older methods? It's the difference between homeostasis and brute force depletion.
16:25Older experimental agents that simply nuke the brain's cholesterol levels. They cause severe collateral damage. The brain still needs cholesterol for vital healthy functions. If you drop it below the normal baseline.
16:37You destroy the integrity of the cell membranes, you impair the synapses, and you cause widespread cellular dysfunction. You essentially damage the healthy parts of the brain trying to starve out the pryons.
16:48Right. You're destroying the village to save it. But a favrins avoids that completely. It restores homeostasis. Because it just opens the exhaust pipe? Exactly. Just enough to clear out the pathogenic, hoarded excess that the prions are exploiting, but it does not deplete the cholesterol below a healthy normal baseline.
17:07It just returns the system to balance. Which honestly opens up a conversation far beyond just prion disease, because dysregulated cholesterol isn't just a CJD problem, is it? Not at all. Dysfunctional brain cholesterol metabolism is a major hallmark across a huge spectrum of devastating neurodegenerative disorders.
17:25Like Alzheimer's. Alzheimer's disease, Huntinson's disease, Huntington's disease, in all of these conditions, impaired cholesterol turnover seems to promote the accumulation of toxic, misfolded proteins.
17:39So regulating this specific CYP 46A1 exhaust pathway could have massive ripple effects across the entire field of neurology. The potential is enormous. In fact, Lodos of Favrins is currently being investigated in clinical trials for early stage Alzheimer's disease, using this exact same rationale.
17:58Just activating the enzyme to enhance turnover and clear the toxic buildup. Exactly. It is genuinely incredible to think that a tiny microdose of a drug approved in the late 90s for a completely different virus could open a totally new front in the battle against neurodegeneration, and it proves exactly why we took this pivot in our series today. Lowering the prion protein is vital, but it is not the only road we can take.
18:20It really isn't. a whole new frontier. That concludes today's deep dive on base by base. Thank you for listening to our exploration of this research. Base by base is brought to you by our dedicated team.
18:32Don't forget to follow us and leave a rating in your podcast app. We'll see you next time.
