A new strategy for diagnosis and therapy of prion diseases

Nobel Prize laureate Stanley Prusiner of the University of California at San Francisco postulated two decades ago that the infectious agentcausing prion diseases (Creutzfeldt-Jakob disease, BSE, chronic wasting disease, and other diseases) consists exclusively of a misfolded protein. This protein, according to Prusiner, multiplies by binding to the normal prion protein and converting it into a disease-inducing form. However, proof that such binding between the normal and of the pathological prion proteins would really occur in a living organism was lacking until now.

This proof of concept was now delivered by the research laboratory of Prof. Aguzzi. The researchers have constructed a modified artificial prion protein to which they attached a fragment of a human antibody molecule. This fragment was then used as a flag to visualize directly the binding reaction. Excitingly, the binding reaction between the pathological and the normal prion protein was extremely selective and discriminatory. This finding paves the way to sensitive methods for the detection and for the early diagnosis of prion infections.

From a therapeutic perspective, the most exciting discovery is that the modified prion protein attached to a human antibody fragment, when expressed in genetically modified mice, significantly hampered prion infection. This means that the modified molecule is capable of interfering with the replication of pathological prion. This effect was very robust: small amounts of the modified protein suffice to inhibit prion replication. These data indicate that the prion fusion protein may serve as a prototype for an novel class of antiprion drugs.

The molecular mechanism of this therapeutic effect has also been clarified by Aguzzi and co-workers. The modified prion protein attaches to the pathological prions, but cannot be converted into a pathological form itself. Therefore, infectious prions are sequestered in an inactive form and cannot replicate.