The Problem with Treating Prions
You may or may not have heard of prions. Understandably so, as little is known about the neurodegenerative disease-causing proteins, despite 30 years of research. While we know that prions are responsible for mad cow disease, Creutzfeldt-Jakob disease (CJD), Alzheimer's disease, Huntington's disease, and Parkinson's disease, we do not know how to treat prion-related diseases. Prion diseases begin with a cellular prion protein (PrPC) which becomes a scrapie associated prion protein (PrPSc). While the PrPC takes on the shape of a normal protein, the PrPSc is an abnormal protein because it becomes misfolded through a process called conversion (see Figure 1 below). The misfolded form of a protein will infect other proteins around them, eventually leaving the brain full of holes. The victim is left with memory impairment, personality changes, movement difficulty, and eventually, death. The solution to any disease is treatment though, and that is where the field of prion diseases is heading.
Figure 1 - Prion Development
Despite researcher's best efforts, there are no medical drugs or therapies to treat prion diseases. The lack of treatment for prion diseases is due to challenges faced when developing a therapy for prion diseases. One challenge is how to get antibodies to cross the blood brain barrier, which prevents substances from entering the brain. Another challenge is selecting the right choice of drug and antibodies to elicit a correct and effective response to the prion proteins. The prevalence of prion diseases is also a challenge. Since they are not extremely prevalent, it can be difficult to test new treatments and set up clinical trials. Much of the research in this field has been conducted on individuals with Alzheimer's disease because it is more prevalent. Many effective treatments for other diseases, such as small molecules, vaccination, antibodies, peptide aptamers, and nucleic acid-based agents, have been tried and have failed to treat prion diseases. Despite this, there is still hope for new advancements in the field.
Immunotherapy is arguably the most promising treatment solution. Prions cannot be destroyed by our immune system unaided. Since prion proteins are composed of a portion of normal proteins, the prion proteins do not activate an immune response. Prions also do not activate B cells, which are immune response cells that play a crucial role in an immune response. However, if an immune response could be triggered, the prion proteins could be destroyed. Immunotherapy does this by activating an immune response as a treatment. This tactic has been used for other diseases, such as cancer, and has promising outcomes. Immunotherapy is very effective in identifying diseased areas of the body with relatively few side effects. In the context of prion diseases, monoclonal antibodies are being used to target the misfolded portion of the prion protein.
Immunotherapy can target prion diseases for two reasons. One reason is that the shape of the misfolded prion proteins is a well-known disease-causing agent. This makes the misfolded protein easily identifiable by therapeutic agents, which are drugs that aim to have curative or preventative properties targeted towards a disease, because the therapeutic agents can target the disease-causing agent. The second reason is that the misfolding of a protein occurs on the cell's surface. Since the protein is found on the cell surface and not within the cell, this makes the protein easily accessible to therapeutic agents. Active immunization and passive immunization are two types of immunotherapies that could be used for prion diseases.
Active immunization is when the immune system produces antibodies for a disease. It is seen as the most practical approach for animal prion diseases. This type of immunization can take days or weeks to develop, but the effects are longer-lasting. Previous research has shown that active immunization is not as safe as passive immunization because it can cause an inflammatory response in the brain. One study used an AN1792 vaccine on mice with Alzheimer's disease to eliminate the misfolding proteins in the brain but had to be stopped due to negative side effects, such as meningo encephalitis and vasogenic edema, which are infections of the brain. After the clinical trial, though, the mice treated with a vaccine showed a reduction in the abnormal proteins. Active immunization is also tricky because the immune system does not recognize the abnormal protein as foreign. Therefore, no immune response is activated. Current research uses drugs to stimulate immune cells, hoping to induce a response.
Passive immunization is giving antibodies to a person for a disease instead of the antibodies being produced by the person immune system. Unlike active immunization, passive immunization develops immediately, but the effects may only last a few weeks or months. The effects only last a short time because the body does not develop memory for what you are immunized against. Therefore, there is a risk of being reinfected by the same pathogen. It is the most practical approach for human prion diseases, but most of the research currently utilizes animal models. One study used antibodies to target different forms of abnormal proteins in Alzheimer's disease but found negative results. Although the experiment failed, the research still contributed to future methods of prion disease clinical trials. For example, it provided insight into future treatments that may be more effective.
Much of the research talked about has ultimately failed in clinical trials for one reason or another. Without these failures, progress towards a treatment could not be made. Research into immunotherapies for prion diseases are ongoing, as an effective treatment solution has not been found. While much of the research done so far has utilized Alzheimer's disease, the similarities to other prion-related diseases will also benefit from this research. All work in neurodegenerative diseases will advance the therapeutic strategies of prions diseases. Many of the challenges faced will be resolved with advancements in technology and new methods for delivering antibodies to the brain. Until then, science will move forward until an effective treatment for prion diseases has been discovered.
If you are interested in learning more about the treatment of prion diseases, I have conveniently linked some awesome websites below!
https://www.mindsunderground.com/muarticles/prions-disease
https://www.smithsonianmag.com/smart-news/prions-are-fascinating-terrifying-and-still-mysterious-180965125/
http://www.prionalliance.org/2013/11/26/what-are-prions/
