Prion diseases

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By Raymond P Roos MD

The fear of an epidemic of variant Creutzfeldt-Jakob disease has challenged the scientific community to identify potential treatments. A number of drugs have been tested in mice that carry PrPSc; however, there remains no confirmed effective treatment for any prion disease (Brown 2002). The finding that turning off expression of PrPSc in the mice rescues them from disease (Mallucci et al 2003) and leads to recovery from cognitive and behavioral symptoms (Mallucci et al 2007) is encouraging and suggests that the disease process is not inexorably fatal after it starts. Experiments showed that knockdown of PrPC following lentiviral delivery of RNAi into the hippocampus of scrapie-infected mice led to a prolongation in survival, with a decrease in behavioral defects and neuropathology (White et al 2008). Another direction in treatment involves the use of dominant negative mutants of PrP, which are thought to interfere with the conversion of PrPC into PrPSc and are also not thought to be converted into PrPSc (Toupet et al 2008). Virus vector delivery of scrapie-infected mice with these mutations led to increased survival and an improvement in behavior. There have also been attempts to knockdown PrP by means of immunotherapy, primarily with antibody directed to all or part of PrP (Roettger et al 2013). These antibodies have been shown to increase lifespan, and in some cases, prolong the incubation period of scrapie mice. Unfortunately, and surprisingly, some of the antiprion antibodies are neurotoxic in animals, a finding that is presently under investigation, and one that might clarify a mechanism by which prions cause disease (Sonati et al 2013). Another promising avenue for treatment is osmotic pump delivery of antisense oligonucleotides into the ventricle (Nazor Friberg et al 2012). Of interest is a recent publication that showed that treatment of a scrapie-infected mouse with a drug that inhibits a key kinase in the unfolded protein response abrogates the development of clinical disease and decreases the neuropathological abnormalities (Moreno et al 2013). The latter study is provocative and clearly needs further investigation. Unfortunately, there is still no recommended treatment to slow the course of Creutzfeldt-Jakob disease or prevent disease from developing in a clinically asymptomatic individual who carries a mutant PRNP gene associated with familial Creutzfeldt-Jakob disease.

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited