Treatment of prion diseases
Prion diseases are rare, terminal brain disorders caused by misfolded proteins that lead to severe neurodegeneration, characterized by spongiform changes in brain tissue. Currently, there is no cure for these diseases; treatments focus primarily on managing symptoms to enhance quality of life. Research efforts are ongoing to find effective therapies, with scientists exploring various molecules and compounds that may inhibit the formation and toxicity of abnormal prion proteins. Some potential treatments being investigated include quinacrine, pentosan polysulphate (PPS), and flupirtine, although results have been inconclusive, with mixed outcomes in clinical trials. Additionally, management strategies may involve supportive measures, such as feeding tubes for those with swallowing difficulties. A key challenge in treating prion diseases is that they are often diagnosed at advanced stages, limiting the effectiveness of interventions. Future approaches aim to diagnose these conditions earlier and potentially prevent the onset of symptoms. Understanding prion diseases remains a complex and evolving area of research, with significant implications for patient care.
Treatment of prion diseases
Definition
Prion diseases are rare and fatal degenerative brain disorders that are caused by mutated proteins in the brain that aggregate and form visible “holes.” These holes show a spongy appearance seen through a microscope, hence the name “spongiform encephalopathies.” Because these diseases are terminal, treatment is meant to control symptoms that may cause discomfort; there is no cure for the disease state. Certain diseases, such as scrapie (a disease of sheep and goats),and two human diseases, Creutzfeldt-Jacob disease (CJD) and kuru, are transmitted by an infectious agent, namely a prion. Variant Creutzfeldt-Jacob disease (vCJD) and Gerstmann-Sträussler-Scheinker syndrome are two familial forms of prion disease and are considered inherited neurodegenerative disorders.
General Considerations
There are no known ways to cure prion diseases; however, scientists around the world are working to develop methods to treat symptoms. Using infectious tissues from cultured cells, researchers have identified hundreds of molecules that inhibit the formation of the abnormal form of prion proteins. Groups of scientists are studying these infectious agents in animals, while other scientists are testing two molecular compounds in CJD patients. Researchers have identified antibodies and fragments of prion protein (short synthetic protein molecules) that can block the conversion of normal prion protein to the abnormal form. If successful, these studies may lead to effective methods to prevent prion infections and to the development of therapies that work either in affected patients or in the presymptomatic phases of disease.
One clinical trial, sponsored by the National Institute for Aging, assessed the potential benefits of the drug quinacrine for human sporadic CJD in the United States. Quinacrine has been used extensively as an antimalarial medication, and it is known to pass the blood-brain barrier. Because the main site of treatment for prion diseases is in the brain, where much of the neuronal damage is caused, drugs administered intravenously need to cross the blood-brain barrier to be effective. However, there is controversial evidence of the success of quinacrine for persons with CJD, as one person reported neurologic improvement. In another study, no benefit was seen in the animals being examined.
Pentosan polysulphate (PPS) is a component found in beech wood and is used generally as an antithrombotic and anti-inflammatory drug. It has helped persons who have thrombotic (blood clotting) disorders and interstitial cystitis (inflammation of the urinary bladder). In vitro experiments (performed in the laboratory on cultured cells) showed that PPS affected the production of prion proteins, their replication, and their cell toxicity. However, the laboratory experiments did not show any effect when used as treatment for humans with prion diseases. Because little is known about how neurons die in persons with prion diseases, it is difficult to understand the mechanism by which this drug may work. In vivo work using PPS on animals has shown that when PPS is given to animals at or near the time of experimental infection, a prolonged time exists between inoculation of infection and the appearance of disease. Some animals have shown complete protection against the development of disease. However, these experiments do not give clear evidence that PPS will have any positive effect on people with prion diseases.
Only a few people have received PPS as treatment for vCJD. These treatments were administered in the United Kingdom. PPS was given through the intracerebroventricular route, because PPS does not cross the blood-brain barrier. One patient had suggestions of improved neurological condition, but judgment is difficult to ascertain, and another patient showed no successful response to the drug. Other scientific papers using this treatment on a few patients have been published, with inconclusive results; however, the research has led to further investigation, though caution is emphasized because of possible side effects and the risk of administering the drug.
Another potential drug is the analgesic flupirtine, which may slow down the cognitive deterioration seen in persons with CJD; however, this drug has not been shown to be significantly effective in increasing the survival rates of persons with CJD.
Much remains to be learned and understood about the use of flupirtine and other drugs for prion diseases after infection has occurred. More needs to be known about the dose and administration of the drug and about what specific diseases may react to the drugs in ways similar to the reactions in in vivo experiments.
Another form of treatment is the use of permanent feeding tubes. To help with symptoms, persons with dysphagia or swallowing difficulties, for example, may need feeding tubes.
Impact
One major dilemma in attempts to treat prion diseases is that persons with the disease are identified long after the disease has advanced. Therefore, treatments are less likely to help with symptoms or to improve the disease state. One approach for future treatment is to intercept the disease well before it deteriorates the brain and to diagnose the disease earlier in the disease state.
Bibliography
Barrett, A., et al. “Evaluation of Qunicarine Treatment for Prion Diseases.” Journal of Virology 77 (2003): 8462-8469.
"Developing Treatments for Prion Diseases." National Institutes for Health, 23 July 2024, www.nih.gov/news-events/nih-research-matters/developing-treatments-prion-diseases. Accessed 4 Feb. 2025.
Doh-ura, K., et al. “Treatment of Transmissible Spongiform Encephalopathy by Intraventricular Drug Infusion in Animal Models.” Journal of Virology 78, no. 10 (2004): 4999-5006.
Rainov, N. G., et al. “Treatment Options in Patients with Prion Disease: The Role of Long Term Cerebroventricular Infusion of Pentosan Polysulfate.” In Prions: Food and Drug Safety, edited by T. Kitamoto. New York: Springer, 2005.
Todd, N. V., et al. “Cerebroventricular Infusion of Pentosan Polysulphate in Human Variant CJD Disease.” Journal of Infection 50 (2005): 394-396.