Transmissible forms of neurodegenerative diseases that are always fatal sounds terrifying, and almost like science fiction. Unfortunately, prion disorders like Creutzfeldt-Jakob disease (CJD) are very real, but thankfully still extremely rare (only about 300 cases per year in the United States). A prion is a type of protein that can trigger normal proteins in the brain to fold abnormally, so studying the rare disorders that result can provide insights into other neurodegenerative diseases, such as Alzheimer’s, which have misfolded proteins. Now, investigators from the University of Zurich and Novartis Institutes for BioMedical Research in Switzerland have reported on finding antibodies targeting the normal prion protein (PrP) molecule in individuals with no history of any associated transmissible spongiform encephalopathies.
Findings from the new study—published recently in EMBO Molecular Medicine through an article titled, “Protective anti‐prion antibodies in human immunoglobulin repertoires“—is significant as it shows that potential immunotherapeutics could be created to help treat this deadly disorder.
“Antibody‐based immunotherapy might be an efficient way for the treatment of prion diseases, for which no cure exists,” the authors wrote. “However, antibodies targeting specific regions of PrP can either be neurotoxic or neuroprotective. Hence, the identification of anti‐PrP antibodies, specifically targeting neuroprotective epitopes, is of high importance for the generation of safe prion immunotherapeutics.”
Prion proteins can be converted into a disease-causing infectious particle-like PrPSc, an aggregated version or isoform resistant to degradation by protease enzymes. Resulting prion diseases, like other neurodegenerative syndromes such as Alzheimer’s disease and Parkinson’s disease, are associated with the accumulation of misfolded and aggregated proteins in the central nervous system. Antibodies against such proteins may be beneficial and offer the potential for therapies against such diseases by targeting the pathological aggregates for degradation by phagocytic cells.
In the current study, the researchers found a small proportion of individuals, 21 of 37,894 hospital patients screened for the presence of anti-PrP IgGs, the most common form of immunoglobulin. Moreover, there was substantial evidence from lack of any history of disease among these individuals that these antibodies were not themselves neurotoxic. That, combined with the lack of such antibodies among people who do carry disease-causing mutations in the PRNP gene coding for prion proteins, suggests they might have cleared unwanted nascent disease prions early in life.
“We identified >6,000 PrP‐binding antibodies in a synthetic human Fab phage display library, 49 of which we characterized in detail,” the authors penned. “Antibodies directed against the flexible tail of PrP conferred neuroprotection against infectious prions. We then mined published repertoires of circulating B cells from healthy humans and found antibodies similar to the protective phage‐derived antibodies. When expressed recombinantly, these antibodies exhibited anti‐PrP reactivity. Furthermore, we surveyed 48,718 samples from 37,894 hospital patients for the presence of anti‐PrP IgGs and found 21 high‐titer individuals. The clinical files of these individuals did not reveal any enrichment of specific pathologies, suggesting that anti‐PrP autoimmunity is innocuous.”
Interestingly, previous research had already shown that anti-PrP antibodies are effective in mice infected with prions and also some human cells, suggesting they might represent a viable therapeutic strategy. However, it has also been demonstrated that the biological effect of anti-PrP antibodies depends critically on which part, or epitope, of the PrP prion recognized by the immune system is targeted.
This current work sought to produce a high-resolution map of neuroprotective epitopes, with the goal of identifying immunotherapeutics that might be effective, as well as safe by avoiding neurotoxic effects. This was achieved by discovering antibodies that targeted both the main globular domain (GD) of the prion protein and its flexible tail (FT). This suggested there was a polyclonal antibody response, offering further evidence for the existence of naturally occurring antibodies against the prion protein in humans.
The resulting immune response capable of clearing nascent infectious prions may then operate analogously to immune surveillance for neoplastic cells that cause cancer. At the very least, the generation of antibodies to the whole set of PrP epitopes provides new tools for studying the mechanism of neurodegeneration conveyed by prions.
“Our data demonstrate the presence of naturally occurring, innocuous anti‐PrP antibodies in humans which may constitute a potential source for the development of effective and safe immunotherapeutics to combat prion diseases,” the authors concluded.