April 23rd, 2024
Written by: Joseph Gallegos
As a starry-eyed 18-year-old college student in Northern Colorado, I received my first chance to work in a scientific research lab studying a kind of brain disease caused by something called a “prion” (pronounced ‘pree-awn’). I was immensely grateful for the opportunity, but a small part of me was somewhat disappointed. I didn’t know anything about the brain and besides, I was really interested in viruses and wanted to join a lab studying HIV. But like most things an 18-year-old doesn’t want to hear, this proved to be a transformative experience for me. Not only because it made me fall in love with the brain and propelled me onto my scientific career, but because it taught me why studying disease matters.
Each year our lab would participate in a charity walk called “Strides for CJD”, an event hosted to bring awareness and raise money for research on Creutzfeldt-Jakob Disease (CJD), the most common human prion disease 1. Human prion diseases include CJD, as well as two other disorders: Gerstmann-Straussler-Scheinker disease and Fatal Familial Insomnia1. These three diseases are very rare, affecting about one in a million people worldwide 1–3. Although they are not common, they are devastating diseases that often go unnoticed until decades worth of the brain slowly dying suddenly leaves a person with severe loss of brain function 4.
Prion diseases are always fatal and everyone at “Strides”, including diagnosed individuals and their families, knew that. But it was never a dreary conversation when I talked with any of them. They were always keen to learn more about their disease and our ongoing research, and I always felt inspired by their courage. Perspective is hard to find when you think of a disease in terms of test-tubes and cell incubators, and not as a person with a voice, and a story, and a smile. There was always a sense of unyielding hope that filled the autumn air as we walked under the elm trees of my college campus. Now for the first time ever, those walkers have more than just hope to stand on, because in January 2024 the first clinical trial testing a drug designed to directly halt prion disease began in the United States 5. But what is a “Prion”, and what were the discoveries that paved this path towards a cure?
What the heck is a “Prion” anyways?
If you have heard of Prions before, it likely means you were either a witness to the “Mad Cow Disease” outbreak of the 1990’s, or you might spend too much time on zombie-apocalypse web forums. That is to say… Prions have developed quite a reputation for themselves since their discovery in the 1980s 6. The main reason Prions have captivated many peoples imaginations is that unlike other brain diseases, prion diseases are infectious: they can spread from individual to individual. Thankfully for us, it doesn’t spread easily like the common cold, it takes specific circumstances for the spread to happen (which I will mention later). The other fascinating property of these diseases is that they are unlike any other infectious disease that has been discovered. They aren’t caused by a virus, or a bacteria, or a parasite, or even a fungi. Prions “live” in our own DNA, and are probably inside your head right now. But I promise that your chances of becoming a zombie aren’t any greater than they were before you knew that.
Prion diseases are caused by one thing, the Prion Protein. The Prion Protein is abundant in all of our brains, being produced at high levels during brain development and throughout adult life 7. So why aren’t we all getting prion diseases? To understand this, we will have to learn a little bit of protein biology. The instructions for making all of the proteins our cells use to survive and carry out their tasks are stored as genes in our DNA (the gene for the Prion Protein is called “PRNP”). When a cell wants to make a protein, it will copy down those instructions as a message in the form of an RNA molecule, and these messages are read by special machines that will design the protein exactly as it was written in the DNA / RNA blueprint. Proteins are initially assembled into a long chain much like beads on a string, and based on the specific chemical properties the blueprints gave them, these chains will ‘fold’ into elaborate 3D shapes. Biologists now understand that it is the shape of a protein that matters the most, because even if a protein originates from the same DNA / RNA blueprint, if it changes shape it can have completely different functions. And it turns out that the Prion Protein is a master at shapeshifting.
For most people, the Prion Protein will always be made into its proper shape and this is the version that is produced abundantly in the brain. However, in some instances it will morph its shape into a lethal and infectious variant of the protein, and this is how it causes disease. Through a puzzling and still unknown process, this infectious Prion Protein can actually make copies of itself, by converting the regular Prion Protein into the same shape as the infectious one1,8. You can think of the infectious Prion like a cookie cutter that seeks out the regular protein and forces it to become the same shape (Figure 1A). This basically allows infectious Prions to replicate themselves, and this process starts a chain reaction causing the number of infectious Prions to increase exponentially, and spread from cell to cell within your nervous system. As a swarm of infectious Prions accumulate over many years, they induce large amounts of stress on the cells in your brain and eventually cause those cells to die.
Where do these infectious Prions come from?
So how does this whole process of prion shapeshifting get kicked off in the first place? The most famous scenario is one that actually represents only 1-2% of total human prion diseases: those where infectious Prions are brought in from an outside source. These “acquired” forms of the disease occur if someone ingests meat that has been contaminated with infectious Prions. This is what occurred during the “Mad Cow Disease” epidemic, but it has also occurred in a tribe of people in Papua New Guinea that historically practiced ritualistic cannibalism, creating a disease called Kuru (again, bad reputation) 1,2,9. Additionally, it was tragically learned that accidental transfer of infectious Prions from one person to another could occur if surgical equipment is not properly decontaminated after brain surgery 2. However, increased awareness and understanding of the hazards that Prions pose to human health has caused cases of acquired prion disease to plummet since the early 2000’s, and scientists now have the tools to detect and prevent the spread of any new outbreaks 2.
Besides eating contaminated meat, an additional 10-15 % of human prion diseases are inherited through mutations in the PRNP gene that make it more likely to shapeshift into the infectious Prion. But the majority of human prion diseases (~85%) occur spontaneously, where there is no clear reason why the infectious Prion was formed and took over the brain. Although prion diseases come in these different categories, that can even result in drastically different symptoms, they are all unified in the requirement that the regular Prion Protein is produced and available as a template to make more. And it is in this shared trait that we now have our first target to stop the disease.
How do you put out a fire?
It has been known for decades now that if you can get rid of the regular Prion Protein, then you will effectively starve any infectious Prions that are around, and no brain disease will develop 10. The removal of the regular Prion Protein doesn’t seem to have any obvious negative effects either, as without it animals live normal healthy lives with no major changes in brain function 7,10. These discoveries led scientists to propose that if you want to stop a prion disease, the best thing to do may be to just stop the brain from making the regular protein itself. Sometimes the easiest way to put out a fire is by taking away the fuel. And that is exactly the goal of the now ongoing clinical trial 5.
This study has enrolled 56 individuals who had a probable or confirmed diagnosis of any prion disease at the time of screening. Each individual will be randomly assigned to receive either a placebo, or the drug known as ‘ION717’, developed by Ionic Pharmaceuticals and pioneering research by Dr. Sonia Vallabh and her husband Dr. Eric Minikel (as an aside, I encourage you to read their personal story because it is an amazing tale of determination and resilience in the face of life altering news). ION717 is designed to stick to the PRNP RNA message like a strip of Velcro, and this will instruct the cells to shred up the RNA resulting in a significant reduction in the amount of prion proteins being made (Figure 1B). Less fuel for the fire. Reassuringly, in rodent models of prion disease treatment with this drug led to Prion-infected mice living 61-98% longer than placebo treated controls 11.
If this drug proves to be effective in humans, it realistically will not be a miracle cure for most. Most prion diseases are not revealed until very late in life, and by the time symptoms show people decline rapidly and die after only 5 months 1. Even if you completely stopped the formation of new infectious Prions in their tracks, the brain would still need to clear out the millions of infectious proteins that have been churning out for decades. However, an important observation from the study of this treatment in mice did show that a single dose given just weeks before mice typically succumb to Prion infection, was enough to prolong their survival by up to 55%11. So for those late-stage individuals, the hope is that this treatment will lower the burden on the brain, giving people a better quality of life and precious time to spend with their loved ones.
The group of people with the best outlook from this treatment are those with a genetic risk of developing prion diseases. Scientists have characterized the exact mutations that increase the likelihood of developing disease, and with genetic testing they can be discovered at a young age, even during pregnancy 12. If the treatment strategy of “ION717” works, it isn’t far-fetched to think that individuals with inherited Prion diseases may be able to live a normal and healthy life. But only time and scientific evidence from the clinical trials will tell us if we can count on that.
The first step onto a long road
It is important to note that this is only a Phase 1 clinical trial, which means its purpose is to test that the drug is reaching the brain, and to make sure that there are no serious adverse side effects that are caused by the treatment. If successful, the following Phase 2 and 3 trials will ramp-up and generate the data we need to show that this drug can actually create a meaningful disruption of the disease, and improving the survival and livelihood of those with it. So while it will still be some time before we can state we have a treatment that halts Prions in their tracks, it is taking the first crucial step towards finding a solution for these devastating diseases. The trial is expected to conclude in October of 2025, but with initial results being collected earlier that same year.
As “Strides” usually happens in the first week of October, I hope with bated breath that next year those walkers will instead be jumping for joy.
References
1. Zerr I, Ladogana A, Mead S, Hermann P, Forloni G, Appleby BS. Creutzfeldt–Jakob disease and other prion diseases. Nat Rev Dis Primer. 2024;10(1):1-16. doi:10.1038/s41572-024-00497-y
2. Watson N, Brandel JP, Green A, et al. The importance of ongoing international surveillance for Creutzfeldt–Jakob disease. Nat Rev Neurol. 2021;17(6):362-379. doi:10.1038/s41582-021-00488-7
3. Will RG, Alperovitch A, Poser S, et al. Descriptive epidemiology of Creutzfeldt-Jakob disease in six european countries, 1993–1995. Ann Neurol. 1998;43(6):763-767. doi:10.1002/ana.410430611
4. Parchi P, Strammiello R, Giese A, Kretzschmar H. Phenotypic variability of sporadic human prion disease and its molecular basis: past, present, and future. Acta Neuropathol (Berl). 2011;121(1):91-112. doi:10.1007/s00401-010-0779-6
5. PrProfile: A Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ION717. ClinicalTrials.gov ID: NCT06153966.
6. Prusiner SB. Novel Proteinaceous Infectious Particles Cause Scrapie. Science. 1982;216(4542):136-144. doi:10.1126/science.6801762
7. Castle AR, Gill AC. Physiological Functions of the Cellular Prion Protein. Front Mol Biosci. 2017;4. doi:10.3389/fmolb.2017.00019
8. Prusiner SB. Prions. Proc Natl Acad Sci U S A. 1998;95(23):13363-13383.
9. Collinge J, Whitfield J, McKintosh E, et al. Kuru in the 21st century—an acquired human prion disease with very long incubation periods. The Lancet. 2006;367(9528):2068-2074. doi:10.1016/S0140-6736(06)68930-7
10. Büeler H, Aguzzi A, Sailer A, et al. Mice devoid of PrP are resistant to scrapie. Cell. 1993;73(7):1339-1347. doi:10.1016/0092-8674(93)90360-3
11. Raymond GJ, Zhao HT, Race B, et al. Antisense oligonucleotides extend survival of prion-infected mice. JCI Insight. 4(16):e131175. doi:10.1172/jci.insight.131175
12. Goldman JS, Vallabh SM. Genetic counseling for prion disease: Updates and best practices. Genet Med. 2022;24(10):1993-2003. doi:10.1016/j.gim.2022.06.003
Cover Photo by: Heung Soon on Pixabay
Figure 1: Created by Joseph Gallegos using BioRender
PennNeuroKnow 
I learn so much from your writing and you make a subject that is unfamiliar so easy to understand. Thank you for all the time you took to compile all of this information. I always am happy when I see your name pop up on here. I know I will get another dose of education.
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