Episode Transcript
[00:00:00] Speaker A: Foreign.
[00:00:20] Speaker B: Welcome to Base by Bass, the papercast that brings genomics to you wherever you are. Thanks for listening and don't forget to follow and rate us in your podcast. Appreciate.
[00:00:27] Speaker C: Yes, thank you for tuning in.
[00:00:29] Speaker B: This is the second of two episodes dedicated to Lito Sousa, the Brazilian aviation communicator behind the channel Evoes y Musicas, Airplanes and Music, who shared publicly in August 2026 that he had been diagnosed with Creutzfeldt Jakob disease.
In our previous episode, we looked at a genetic silencing approach, now entering its first human trial.
Today we go back to the study that opened this whole field.
The experiment that first showed in living animals that lowering prion protein after symptoms have already begun can still change the course of the disease.
[00:01:03] Speaker C: Right.
It's such a critical piece of the puzzle.
[00:01:05] Speaker B: So we're asking one massive question today. Once a prion disease has actually started, you know, once it's taken hold, is it definitively too late?
[00:01:12] Speaker C: Yeah. And historically, I mean, for decades, for any rapidly progressive neurological condition like this, the medical consensus was just a devastating. Yet it was always assumed to be too late. The narrative is just this steady, unstoppable decline.
[00:01:28] Speaker B: Like a runaway train or something.
[00:01:29] Speaker C: Exactly. But the research we're unpacking today, it completely reframes that assumption. It asks if we can intercept a fatal brain disease that has already, you know, breached the walls and started causing severe structural damage.
[00:01:43] Speaker B: And before we get into how they actually tested this, we need to talk about who did the testing. Because this wasn't just a small side project, right?
[00:01:49] Speaker C: Oh, no, not at all. The collaboration behind this work is a huge part of why it's so robust.
So we're talking about a combined effort from the NIIIED Rocky Mountain Laboratories, which was led by Byron Coffey, along with the Broad Institute team of Sonia Valab and Eric Minocol and Ionis Pharmaceuticals.
[00:02:06] Speaker B: So that's government, academia, and industry all teaming up.
[00:02:10] Speaker C: Yeah. It's a rare and really powerful thing to see those three pillars converging on a single highly focused goal. And this specific paper from 2019, it literally became the scientific foundation on which all the current genetic silencing trials base were built.
[00:02:27] Speaker B: Wow. Okay, so to understand what they pulled off, let's establish what we're actually fighting here. Prion disease is.
It's terrifyingly unique. I always kind of explain it using a zombie analogy.
[00:02:37] Speaker C: Oh, I like that.
[00:02:38] Speaker B: Yeah. So in our bodies, we naturally produce this normal cellular protein called prp. It's just hanging out mostly in the central nervous system, anchored to the Cell membranes. It's just a normal guy.
[00:02:49] Speaker C: Right, Minding its own business.
[00:02:51] Speaker B: Exactly. But in prion disease, one of those normal PRP proteins misfolds. It twists into this dangerous rogue shape.
[00:02:59] Speaker C: Yeah, prpse.
[00:03:00] Speaker B: Right. And that rogue protein acts like a zombie. So it bumps into a normal PRP protein, binds to it, and basically bites it, forcing that normal protein to misfold as well. So now you have two zombies, and
[00:03:12] Speaker C: then four, and then eight.
[00:03:13] Speaker B: Right. It triggers this relentless exponential chain reaction. They clump together, form these toxic aggregates, and ultimately cause massive neuronal death.
[00:03:23] Speaker C: The molecular mechanism is truly that insidious. And what's really challenging is how this chain reaction even starts. In the real world, we generally classify prion diseases into three etiologies.
[00:03:33] Speaker B: Okay, what are they?
[00:03:34] Speaker C: First, you have the acquired form, which is incredibly rare today. That's when someone is exposed to external prions, like through contaminated surgical instruments or historically eating infected meat. Which led to variant circumstances.
[00:03:48] Speaker B: Right, the mad cow era.
[00:03:49] Speaker C: Exactly. Second, there are genetic forms. This is where a specific inherited mutation in the PRNP gene makes a person's normal PRP protein unstable. So it's highly susceptible to just spontaneously misfolding on its own.
[00:04:03] Speaker B: But those two acquired in genetic. That's not most people, right?
[00:04:07] Speaker C: No, the vast majority, roughly 85% of human cases, are entirely sporadic.
[00:04:12] Speaker B: 85%?
[00:04:13] Speaker C: Yeah. There's no genetic mutation from a parent, no exposure to contaminated material. It's just this incredibly unlucky biological event where a single wild type protein randomly misfolds and kicks off the whole fatal cascade.
[00:04:26] Speaker B: That is so scary. Just a random roll of the biological dice.
[00:04:29] Speaker C: It is. But here is the critical. Regardless of whether it's acquired, genetic or sporadic, the underlying vulnerability of the disease remains exactly the same.
[00:04:38] Speaker B: Meaning the disease still needs normal proteins to convert.
[00:04:41] Speaker C: Exactly. The prying contagion relies entirely on the body's own continuous production of normal PRP protein. It needs fuel.
[00:04:50] Speaker B: So, okay, if the disease is completely dependent on our own biology supplying the fuel, the obvious question is, can we just turn off the tap? Like, if we stop making normal prp, does the disease halt? But wait, don't we need that protein? I mean, our brains are full of it.
[00:05:05] Speaker C: You'd think so, right? It's a very logical concern. But. But genetics has actually heavily validated this therapeutic hypothesis. Decades of research show that the normal PRP protein is surprisingly dispensable.
[00:05:17] Speaker B: Dispensable? Like we can just live without it?
[00:05:19] Speaker C: Yeah. Scientists have engineered knockout animals, mice, goats, cattle, that completely lack the prion gene. They produce zero PRP and they are perfectly healthy.
[00:05:28] Speaker B: Wait, really? A whole cow with no prp?
[00:05:30] Speaker C: Yep. They develop normally, their neurological function is fine, normal lifespans. And we even have robust genomic data from human populations showing individuals who carry loss assumption variants.
[00:05:40] Speaker B: So people walking around right now.
[00:05:41] Speaker C: Yes. Essentially, they have one copy of their prion gene turned off, so they produce half the normal amount of the protein. And they are totally healthy. No neurological deficits whatsoever.
[00:05:51] Speaker B: Oh, wow. So we're manufacturing this protein, but our central nervous system doesn't strictly need it to survive.
That makes PRP like the perfect drug target, doesn't it?
[00:06:01] Speaker C: It's an unusually good target, yes, because the protein is dispensable, but the disease absolutely requires it.
[00:06:08] Speaker B: So if we eliminate it, the disease stops spreading and the patient doesn't suffer some catastrophic side effect from losing the protein.
[00:06:15] Speaker C: That's the theory. Exactly.
[00:06:16] Speaker B: Which brings us to the actual tool this 2019 team used to try and turn off that tap antisense oligonucleotides, or ASOS.
[00:06:24] Speaker C: Right.
[00:06:25] Speaker B: Now, for those cracking along, we know that DNA transcribes into messenger rna, and that RNA is then translated into a protein.
The goal here isn't to alter the DNA itself. Right. We're trying to intercept that RNA message before the PRP protein can even be built.
[00:06:39] Speaker C: Precisely. ASOs are basically these synthetic single stranded strings of nucleic acids. They are designed with a specific sequence that is perfectly complementary to the target messenger rna, in this case, the MRNA for the PRP protein.
[00:06:55] Speaker B: So it's like a matching puzzle piece.
[00:06:56] Speaker C: Yes. When the ASO enters the cell, it seeks out and binds directly to that target mRNA. This forms a DNA RNA heteroduplex.
A heteroduplex? Just a hybrid molecule. And this hybrid acts like a flare for the cell's native immune system. It triggers an enzyme called RNase H1.
[00:07:15] Speaker B: Okay.
[00:07:16] Speaker C: And that enzyme recognizes this abnormal double stranded structure and just cleaves the RNA strand. It destroys the instructions before the ribosome can ever translate it into the prion protein.
[00:07:26] Speaker B: Oh, that's brilliant. So the drug doesn't just block the rna, it actually recruits the cell's own cleanup crew to shred the blueprint.
[00:07:32] Speaker C: Exactly. It's a highly efficient mechanism.
[00:07:34] Speaker B: But. And I have to push back a bit on the timeline here, because we've known about ASOs for a while, right? And RNA interference technologies like Cerno, we've known for decades that PRP is the required fuel. So why wasn't this solved, like, 15 years ago?
What were the historical roadblocks that made this business specific? 2019 paper. Such a big deal.
[00:07:55] Speaker C: While earlier researchers were practically flying blind, they ran into a massive wall of methodological and chemical limitations. Like you mentioned, cerna, Small interfering rna. It struggled immensely with central nervous system delivery.
[00:08:09] Speaker B: Because the brain is hard to get into.
[00:08:11] Speaker C: Exactly. Brain tissue is notoriously difficult to penetrate. CERNA molecules just could not achieve widespread distribution. They'd stay completely localized near the injection site.
[00:08:21] Speaker B: Oh, so they'd only treat, like, one tiny spot in the brain.
[00:08:23] Speaker C: Right. Which isn't helpful for a disease spreading everywhere. ASOS offered a way forward because they can be chemically modified by altering the sugar backbone of the nucleotides. Scientists made ASOS highly stable in the cerebrospinal fluid.
[00:08:36] Speaker B: So they wouldn't just get immediately chewed up by enzymes.
[00:08:39] Speaker C: Precisely. But even with those chemical modifications, the early ASO experiments in prion disease were planned, Plagued by major unresolved issues.
[00:08:48] Speaker B: Yeah. Looking at the background, there were three major historical hurdles that stood out to me, and this 2019 team set out to explicitly solve them, Right?
[00:08:56] Speaker C: Yes.
[00:08:56] Speaker B: So the first was mechanism ambiguity. Like, past studies would give these early generation compounds to mice. They'd see a slight extension in survival, but they had no idea why. Like, was the drug actually triggering RNAs H to lower the RNA, or was it just physically sticking to the misfolded prions?
[00:09:13] Speaker C: Right, that physically physical sticking is what we call an aptomeric effect. Prions are notoriously sticky proteins, and nucleic acids can sometimes bind to them nonspecifically.
[00:09:22] Speaker B: Like molecular glue.
[00:09:23] Speaker C: Exactly. And if a drug is just acting like glue, temporarily slowing down the aggregation, that is not a reliable or scalable pharmacological mechanism. You need definitively targeted genetic silencing, not just random chemical interference.
[00:09:37] Speaker B: Okay, so that was hurdle one. And even when they tried to figure that out, they hit the second massive hurdle. Delivery toxicity.
[00:09:43] Speaker C: Oh, this was a huge problem.
[00:09:45] Speaker B: The old studies relied on continuous intraventricular infusion. Meaning they were surgically implanting these tiny osmotic pumps into the brains of the mice.
[00:09:55] Speaker C: Yes, to drip the drug in constantly.
[00:09:58] Speaker B: But the pumps themselves were so harsh, they caused so much tissue damage and necrosis, that half the mice were dying from the complications of the delivery system long before the prion disease even killed them.
[00:10:10] Speaker C: Which naturally leads to the third and really the most clinically devastating hurdle. Because the delivery method was so toxic and the early drugs weren't optimized, researchers could only show a survival benefit if they treated the animals immediately, sometimes literally, the day after they were infected.
[00:10:25] Speaker A: Wow.
[00:10:26] Speaker B: Day one.
[00:10:26] Speaker C: Yeah. The mice simply Wouldn't live long enough to test late stage efficacy. So they could never answer the most important clinical question, which is, does this drug work after the disease is already deeply established?
[00:10:38] Speaker B: And that is the crucial question for human patients, because going back to what you said earlier, 85% of human cases are sporadic. People have absolutely no idea they are developing prion disease until the cognitive and motor symptoms show up. By the time a patient gets a diagnosis, the neurological fire is already raging.
[00:10:55] Speaker C: Exactly.
[00:10:56] Speaker B: So to finally overcome these failures, the 2019 team designed this radically different, highly controlled methodology.
They infected their mouse cohorts intracerebrally with a very specific aggressive strain of prions known as the RML strain.
[00:11:11] Speaker C: Right. The Rocky Mountain Lab strain. It's a very standard, well characterized model. And to solve the delivery toxicity issue, they entirely abandoned the continuous osmotic pumps.
[00:11:21] Speaker B: Thank goodness.
[00:11:22] Speaker C: Yeah. Instead they used bolus intracerebroventricular injections, or ICV doses.
[00:11:28] Speaker B: Needing just a shot.
[00:11:29] Speaker C: Yeah.
[00:11:29] Speaker B: Yes.
[00:11:29] Speaker C: Spaced out single injections of the ASO delivered directly into the fluid filled ventricles of the brain. It's a rapid delivery of a concentrated dose, relying on the chemical stability of the modern ASO to just circulate naturally through the cerebrospinal fluid and permeate the tissue over time.
[00:11:45] Speaker B: So much less invasive. And they engineered two active ASOs for this experiment. Let's call them active ASO1 and active ASO2. They targeted different regions of the mouse gene, I assume to make sure the effects weren't just a fluke of one specific sequence.
[00:12:02] Speaker C: Exactly. But the most brilliant part of their methodology, I think, was the inclusion of a control aso.
[00:12:08] Speaker B: Yes, the scrambled one.
[00:12:09] Speaker C: Right. This control molecule had the exact same chemical modifications, the same altered sugar backbone, but they scrambled the nucleotide sequence so it didn't match any RNA transcript in the mouse genome. It was just gibberish, basically. Yeah.
And the control ASO was the ultimate test for that first historical mechanism ambiguity. Because if the scrambled ASO also extended survival, it would mean the therapeutic effect was just that apomeric sticky interaction.
[00:12:37] Speaker B: Right. I mean, the chemistry itself was just gumming up the works, not actually silencing the gene.
[00:12:41] Speaker C: Right. But if only the active ASOs worked, the mechanism was definitively RNA lowering.
[00:12:47] Speaker B: Okay, so let's look at the actual experiment phase basis. The first was the prophylactic arm, designed to test pure prevention. They gave these bolus injections every 60 to 90 days, starting 14 days before the mice were even infected.
[00:13:00] Speaker C: Yes.
[00:13:00] Speaker B: And the numbers from this prophylactic arm are Absolutely staggering. By continuously suppressing the normal PRP protein before the infection could take hold, the active ASOS delayed the onset of clinical signs by up to 99%.
[00:13:14] Speaker C: It's incredible. And they extended all cause survival, which measures how long the animals lived overall, by 61% to 98% compared to the saline treated control mice.
[00:13:25] Speaker B: 98%. That's basically doubling their lifespan.
[00:13:27] Speaker C: It is. In the context of a universally fatal, rapidly progressive neurodegenerative model, nearly doubling the lifespan of an infected animal is just a monumental biological achievement.
[00:13:38] Speaker B: And what about the scramble control ASO?
[00:13:40] Speaker C: It did absolutely nothing.
0. The mice treated with the control ASO progressed and succumbed to the RML prions at the exact same furious rate as the mice given a placebo saline injection.
[00:13:51] Speaker B: Which is exactly the definitive proof they needed.
[00:13:54] Speaker C: Yes. It confirmed without a shadow of a doubt that the survival extension was driven entirely by the targeted lowering of PRP rna.
[00:14:02] Speaker B: Wow.
[00:14:03] Speaker C: Not by any random chemical stickiness. They proved the mechanism was sound.
And by using the Bolas injections, they proved the delivery method was vastly safer than the old pumps.
[00:14:13] Speaker B: But as incredible as that prophylactic arm is, it still represents a best case scenario. It's treating the fire before the match is even struck.
[00:14:21] Speaker C: Right.
[00:14:22] Speaker B: The true holy grail of this paper is the delayed treatment arm. What happens when the house is already burning down? So they took a cohort of mice and waited a full 120 days post infection before giving a single treatment. And just to give context on that timeline, these RML infected mice typically only survive about 160 days in total.
[00:14:40] Speaker C: Yeah, that's important to understand. Treating at 120 days means intervening when the disease has already run 75% of its terminal course.
[00:14:47] Speaker B: Right.
[00:14:47] Speaker C: At 120 days post infection, these mice are on the absolute precipice of frank clinical signs. The neuropathology is already severe. If you look at the brain tissue of a mouse at this stage, you observe extreme spongiform vacation.
[00:15:01] Speaker B: Spongiform. So literally like a sponge.
[00:15:02] Speaker C: Exactly. The toxic prion aggregates cause the neurons to die and leave behind these microscopic holes, turning the intricate architecture of the brain into a sponge like texture. And alongside that, the brain is undergoing massive astrogliosis.
[00:15:17] Speaker B: What's that?
[00:15:18] Speaker C: Astrocytes are the support cells of the brain, and they become hyperreactive. In this desperate inflammatory response to the widespread neuronal injury, the tissue is heavily burdened with misfolded PRP deposits. It's a brain in the midst of a catastrophic structural collapse.
[00:15:33] Speaker B: And they took these heavily compromised mice at 120 days and gave them a single bolus injection of active ASO1.
[00:15:39] Speaker C: Yes.
[00:15:40] Speaker B: And the results here are the most clinically vital data points in the entire study. That single late stage injection extended survival by 55%.
[00:15:48] Speaker C: It's astounding.
[00:15:49] Speaker B: To put raw numbers on it, these mice lived an average of 87 days longer than their saline treated counterparts. It took an actively dying brain and pushed back the inevitable by nearly three months from one isolated intervention.
[00:16:01] Speaker C: It is a profound finding because it absolutely shatters the assumption that late stage treatment is completely futile. Yeah, but we do need to look at the nuances of the data. The researchers were incredibly transparent about a specific limitation in this delayed treatment arm.
[00:16:16] Speaker B: Right. I noticed that too. With active ASO2.
[00:16:19] Speaker C: Yes. While ASO1 produced that massive 55 survival extension, active ASO2 actually proved to be highly toxic at the 120 day mark.
[00:16:29] Speaker B: Oh, wow.
[00:16:30] Speaker C: Yeah. The mice given ASO2 at this late stage experienced a sudden severe clinical decline and died within days of the injection. Wait.
[00:16:37] Speaker B: But ASO2 worked beautifully in the prophylactic arm. Why would it be lethal at 120 days?
[00:16:42] Speaker C: It's a sobering reality of pharmacology. The ASOs utilized in this study were early proof of concept tool compounds. They were not polished, highly optimized drugs ready for the clinic. But more importantly, it underscores how fragile a deeply damaged central nervous system truly is.
[00:16:58] Speaker B: So a healthy brain, or a brain very early in the infection, can tolerate the chemical stress of the drug, but a brain riddled with microscopic holes just can't handle it.
[00:17:08] Speaker C: Exactly. The tolerability profile of any drug completely changes when the target organ is actively failing. And building on that, we must state plainly that these are results in a mouse model. An extension of survival in a mouse, Even a dramatic 87 day extension is not a cure.
[00:17:25] Speaker B: Right. Extending survival is not the same as cure or reversal.
[00:17:27] Speaker C: Right. The ASO therapy slows down the progression by starving the disease of its fuel. But it does not reverse the damage already done. It cannot bring dead neurons back to life.
[00:17:37] Speaker B: It's buying critical time, but it's not rebuilding the house.
[00:17:40] Speaker C: No, it's not.
[00:17:42] Speaker B: So how do we trace the line from a 55% survival extension in a mouse to actual human medicine? Like, what did this 2019 paper ultimately provide for researchers trying to design a clinical trial today?
[00:17:54] Speaker C: It provided a massive foundation. First, because the control ASO proved the mechanism is unequivocally RNA lowering, we now have a viable biomarker in human trials for neurodegenerative diseases. It is notoriously hard to measure if a drug is actually working in inside the brain. But with this mechanism, researchers don't have to guess. They can perform a lumbar puncture and measure the concentration of normal PRP in a patient's cerebrospinal fluid.
[00:18:20] Speaker B: Oh, so if the normal PRP levels drop, they know definitively that the drug is hitting its target.
[00:18:25] Speaker C: Exactly. Having a direct, measurable biomarker is a huge advantage. And the second thing is the delivery method itself. By proving that bolus dosing works, the they validated a highly translational approach in humans. This translates to periodic lumbar punctures, spinal taps every few months, rather than needing invasive hardware implanted in the skull.
[00:18:46] Speaker B: Which we already do for other therapies, right?
[00:18:48] Speaker C: Yes. This exact method is used to deliver life saving ASO therapies for other severe conditions like spinal muscular atrophy.
[00:18:55] Speaker B: And this research was the direct catalyst that led to Ion 717, an advanced aspect antisense drug developed by Ionis that successfully transitioned into human testing. In fact, in 2026, the PRI profile trial for Ion 777 was reopened with an additional dosing cohort. But we have to be exceptionally clear here. Preliminary safety data in a clinical trial is exactly that. Preliminary safety data. It does not establish efficacy. As of right now, no PRP lowering drug has yet been shown to help human patients.
[00:19:26] Speaker C: Right. No drug has shown it can alter the disease course in humans. Yet we are very much still in the testing phase. And the success of any future therapies relies almost entirely on the speed of clinical diagnostics.
[00:19:38] Speaker B: Because every day matters.
[00:19:39] Speaker C: Every single day. Even if an ASO can alter the disease course at late stages, every day of lost neurons in a human patient is completely irreplaceable. The 2019 paper implicitly highlights the absolute necessity, necessity of rapid diagnostics, specifically pointing to the RTQIC assay. Right?
[00:19:57] Speaker B: Rtqic, that's the test that can detect misfolded prions in human spinal fluid with incredible sensitivity.
[00:20:04] Speaker C: Yes, but for it to matter, neurologists have to know to look for prion disease much earlier. When a patient presents with sudden, rapidly progressive dementia, the RTQYIC assay needs to be deployed immediately, not as a last resort.
[00:20:16] Speaker B: So the therapeutic window is the most critical variable.
[00:20:19] Speaker C: It is.
[00:20:19] Speaker B: And really, that's the central insight of this whole deep dive. To summarize it in just a couple sentences, prion diseases are ruthless and fast. But this research proved that the window after symptom onset may not be completely closed. Intercepting the disease, by knocking down its genetic fuel, can still significantly alter the course, even when pathology has already begun.
[00:20:40] Speaker C: It cracked open a door that the medical field assumed had been permanently shut for decades.
[00:20:45] Speaker B: Which leaves me with a lingering thought that extends far beyond just prion disease.
If we can engineer a sequence specific molecular interceptor to turn off a single protein, if we can halt one of the most aggressive, untreatable fatal brain diseases simply by starving it of its genetic fuel, what other fatal untreatable diseases hiding in our DNA are just waiting for the right RNA switch to be flipped off?
[00:21:08] Speaker C: It's the exact question driving the bleeding edge of genomic medicine.
[00:21:11] Speaker B: Today we close this pair of episodes where we began with LedosUSA to the investigators and sponsors running prion disease trials at Ionis, at the Broad Institute, and at the centers collaborating with them.
There is a patient in Brazil on a waiting list and a community following your work with real attention.
We know that trial enrollment is decided by protocol criteria and clinical judgment, not by public appeals, and we are not asking anyone to set those aside. We are asking that access outside the United States be kept in view as these programs expand expand. Because prion disease does not respect borders and neither should the search for a treatment to listeners. The CJD foundation supports patients and families worldwide, and the trials discussed in these two episodes are registered publicly on ClinicalTrials.gov Nito Obrigado this pair of episodes is for you. This episode was based on an Open Access article under the CCBY 4.0 license. You can find a direct link to the paper and the license in our episode description. If you enjoyed this, follow or subscribe in your podcast app and leave a five star rating. If you'd like to support our work, use the link in the description now. Stay with us folks.
[00:22:35] Speaker A: Late night benches, glass and steel A quiet hunter you can't feel One wrong foot makes shadows grow in fragile circuits moving slow but on the screen a pattern clears a simple cut through tangled fears Turn the message down at the source and change the ending change the course Silence the spark, slow the storm Lower the signal keep the form if the script won't shout, the fire won't start we buy back time we guard the heart Silence the spark Let dawn arrive.
A measured dose then wait and see Threads of warning in chemistry not by luck, not by disguise Guys, it's RNA where the answer lies Even when the damage is written in the halls Even when the night feels heavy on the walls you can still pull the volume from the pain Slow the mistful break the chain silence the spark Slow the storm.
Lower the signal Keep the form less of the maker, less of the mark.
Misfolded mountains fade to dark Silence the spark.
Little life extend hold the light and then the end.
