Approaches to Treating Prion Disease

APPROACHES TO TREATING PRION DISEASE

At present there is no effective treatment for any of the prion diseases, although a variety of agents are being tested. Relatively few drugs cross the blood-brain barrier effectively. Nonetheless, random screening of those known to do so revealed that both quinacrine and chlorpromazine eliminate prions from infected animal brain cells in culture. (Quinacrine is a rarely used antimalarial drug, and chlorpromazine is widely used to treat schizophrenia.) Unfortunately, they do not cure the disease in whole animals. Several high-tech approaches to dealing with prion diseases are in progress, although none has yet reached clinical use.

Removal of prions from infective material is an alternative approach. Filters have recently been developed that remove prions. These were developed by screening combinatorial libraries for ligands that bound prion protein. The ligands are attached to resins and placed in columns for filtration of blood or other liquids that might contain active prions. When scrapie-infected hamster blood was injected into hamsters, 15 of 99 were infected, but if the blood was first filtered through a column of affinity resin L13, none of 96 hamsters were infected.

RNA interference  is widely used to suppress gene expression in laboratory studies. It is possible to generate siRNA that will suppress expression of the Prnp gene in mice. In order to generate the siRNA in prion-infected cells, a retrovirus vector was used that expresses short hairpin RNAs. These are processed in the target cells by Dicer to give the siRNA. This in turn triggers RNA interference directed against Prnp mRNA, which is degraded. Retroviral vectors were chosen because they can infect nongrowing cells, such as those of the nervous system. At least in mice, intracranial injection of the vectors was able to reduce prion levels and prolong survival.

Knocking out the prion gene in livestock is another approach to eliminating prion disease. Transgenic mice lacking both copies of the Prnp gene were engineered several years ago. They grow and develop normally. They are unable to make prion protein and are resistant to infection by pathogenic prions. This confirmed that new (and normal) prion proteins are first made by the host cell, before changing conformation during infectious prion disease.

Although the prion gene is not needed for survival and its role is still unclear, it does appear to be involved in long-term memory and spatial learning.

Recently, cattle lacking both copies of the Prnp gene have been engineered and after 2 years are normal in growth and development. Brain cells from such animals are resistant to prion infection. Prnp knockout livestock could be used to provide prion-free products, if transgenic animals are approved as a source of human food.