Rare Diseases Part IX: A Look at Prion Diseases

This blog series explores specific rare diseases and how CDMOs such as SK pharmteco can support their treatment. In this entry, we examine an entire category: prion diseases. These disorders are rare, fatal, and biologically unique. You can find previous entries here.

Understanding Prion Diseases: The Origins and Spectrum

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative disorders caused by misfolded proteins. Unlike infections caused by bacteria or viruses, prion diseases stem from an abnormal version of the prion protein (PrP). This misfolded protein triggers a chain reaction, causing normal proteins to misfold and accumulate in the brain. The result is progressive neural damage and severe neurological decline^.^1-4

Scientific interest in prions surged in the late 20^th century after the outbreak of bovine spongiform encephalopathy (BSE), commonly known as “mad cow disease”, and its human counterpart, variant Creutzfeldt–Jakob disease (vCJD). These events highlighted the global health risks of prions and accelerated research into their biology, transmission, and cross-species impact.⁵

Tracing the Origins: From Scrapie to the Protein-Only Hypothesis

The history of prion diseases dates back to the early 18^th century, when scrapie was first identified in sheep and goats.6 In 1920, the first human case of Creutzfeldt-Jakob disease (CJD) was documented, followed by other conditions like kuru.⁶

A breakthrough came in the 1980s when Stanley Prusiner proposed the “protein-only” hypothesis. He demonstrated that the infectious agent in scrapie was a protein, not a virus or bacterium, and that it could propagate infectivity without nucleic acids.⁷ Though initially controversial, this model is now widely accepted and provides the foundation of modern prion biology.⁷

Are All Prion Diseases Rare?

Yes. All known prion diseases are rare. Most affect only one to two people per million worldwide each year. Although uncommon, prion diseases remain a priority for researchers due to their severity, lack of treatment options, and potential to cross-species transmission.

How Are Prion Diseases Transmitted?

Transmission Mechanism: Pathways to Neurodegeneration

Prions spread through several routes:

Oral ingestion is the primary mode in natural settings, in disease like scrapie and chronic wasting disease (CWD), prions enter through the digestive tract, are captured by M cells in gut-associated lymphoid tissues and transported to the brain via the peripheral nervous system.^8,9

Latrogenic transmission in humans has occurred through contaminated surgical instruments, cadaveric growth hormone, dura mater grafts, and corneal transplants.⁹

Variant CJD (vCJD) emerged from consuming beef contaminated with BSE prions, demonstrating prion’s ability to cross species barriers.¹⁰

Environmental Persistence and Risk:

Animal prion diseases like CWD pose long-term environmental risks. Infected animals shed prions in saliva, urine, and feces, which can remain infectious in soil for years.¹¹ This persistence complicates containment and increases transmission risk in wildlife populations.

Transmission Dynamics: Strains and Species Barriers

Prion diseases exhibit remarkable strain-specific behavior and species-dependent infectivity. Prions resist conventional inactivation methods, making safe handling and decontamination challenging.⁶

Mechanistically, different prion strains vary in their PrP^Sc conformations , which affect transmission efficiency, incubation periods, and disease phenotypes.¹² While species barriers exist, they are not absolute. The BSE-vCJD transmission in humans illustrates how prions jump species under certain conditions .¹³

For CDMO professionals, these biological realities demand strict operational controls: validated decontamination protocols, rigorous process containment, robust environmental controls, , and extensive risk assessments integrated into R&D and manufacturing workflows.

Examples of Prion and Related Diseases¹

Creutzfeldt–Jakob Disease (CJD): The most common human prion disease, characterized by rapid dementia, motor dysfunction, and fatal progression within a year.

Variant Creutzfeldt–Jakob Disease (vCJD): Associated to BSE exposure, it typically affects younger individuals and often begins with psychiatric symptoms and progresses to neurological decline.

Kuru: Historically transmitted through ritual cannibalism in Papua New Guinea, provided critical insights into prion transmission.

Fatal Familial Insomnia (FFI): A genetic prion disease caused by PRNP mutations, leading to progressive insomnia and autonomic failure.

Gerstmann–Sträussler–Scheinker Syndrome (GSS): A hereditary disorder, involving progressive ataxia and dementia with slower progression than CJD.

Bovine Spongiform Encephalopathy (BSE): A cattle prion disease with significant public health implications due to its link to vCJD in humans.

Chronic Wasting Disease (CWD): Affecting deer, elk, and moose, this disease continues to spread in North America, raising concerns about potential human transmission.

Gene Therapy and Small-Molecule Approaches

Gene Therapy Approaches

Prion diseases result from the conformational conversion of the cellular prion protein (PrPC^C) into its pathogenic isoform (PrP^Sc). Since PrPC^C is required for prion propagation, reducing or eliminating its expression has emerged as a central therapeutic strategy.

Antisense oligonucleotides (ASOs): Raymond et al. (2019) showed that Prnp knockdown significantly delayed disease onset and extended survival in prion-infected mice.¹⁴

RNA interference: Also demonstrated similar neuroprotective effects by rescuing neuronal dysfunction and prolonging survival.¹⁵

CRISPR/Cas9 genome editing: Proposed to disrupt PRNP or introduce protective alleles, especially for individuals carrying pathogenic variants such as E200K or D178N.¹⁶

Population data suggest that heterozygous PRNP loss-of-function variants are well tolerated, supporting the feasibility of partial knockdown.¹⁷ These studies highlight gene therapy as a promising avenue for both prophylactic and disease-modifying intervention.

Small-Molecule Therapeutics

Small molecules offer a complementary strategy to gene therapy by targeting prion propagation or enhancing clearance of misfolded proteins. Early candidates such as quinacrine showed promise in vitro by inhibiting prion replication, but failed to demonstrate clinical benefits due to poor pharmacokinetics and rapid resistance.¹⁸ Similarly, pentosan polysulfate was tested in compassionate-use trials, but demonstrated limited efficacy.¹⁹

Recent efforts have shifted toward rationally designed ligands and high-throughput screening. For example, Kuwata et al. (2007) identified binding “hot spots” in PrP that small molecules could stabilize, preventing its conversion to the pathogenic form.²⁰ Other compounds work indirectly by enhancing autophagy or proteasomal degradation, promoting the clearance of PrP^Sc aggregates.²¹ Although no small molecule has yet shown definitive clinical efficacy, advances in structure-guided design and blood–brain barrier penetration continue to produce more promising candidates.

Complementary Approaches: Gene Therapy + Small Molecules

Gene therapy and small molecule interventions represent complementary approaches to prion disease. Gene therapy targets the root cause by reducing PrP expression, while small molecules offer acute modulation of misfolding, aggregation, and clearance. Future therapeutic strategies may integrate both approaches to achieve durable disease modification in these otherwise intractable disorders.

Moving Research Forward

Prion diseases exemplify the challenges of rare disease research: complex biology, diagnostic uncertainty, and urgent unmet medical needs. Despite the lack of approved treatments, advances in molecular biology, protein science, and therapeutic innovation continue to shed light on the mechanisms of misfolding and aggregation, laying the groundwork for future interventions.

Whether you are advancing gene therapies, small molecule programs, or exploring innovative approaches to prion disease, SK pharmteco is here to help. Stay informed, collaborate across disciplines, and help drive innovation in one of the most challenging areas of neurodegenerative disease.

Connect with our expert team today to explore how our expertise and capabilities can support your research and development goals.