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Institute for Research in Biomedicine
Istituto di Ricerca in Biomedicina

Via Vincenzo Vela 6 - CH-6500 Bellinzona
Tel. +41 91 820 0300 - Fax +41 91 820 0302 - info [at] irb [dot] usi [dot] ch

The Good, the Bad and the Neuroprotective – from IRB a computer-designed antibody to cure prions

on Thursday, October 11, 2018

Prion diseases affect the brain, causing neurodegenerative problems that always lead to death. They attracted attention in the late 90s due to the “Mad Cow” scare. Today they are not only incurable but even largely not understood. Although Mad Cow disease is not a threat anymore due to veterinary control, human prion diseases (hereditary and sporadic forms) kill about 400 people per year in Europe.

The group of Luca Varani, at the IRB-USI of Bellinzona, Switzerland, produced an artificial antibody capable to block prions in the laboratory, even when administered when signs of infectious neurodegeneration are already apparent in the cellular models.

In the last few years researchers from all over the world have put great hope in antibody-based therapies. Antibodies, natural molecules of the immune system, developed so far are can protect from prion in laboratory tests only If administered before the infectious agent, prion itself. This complicates their therapeutic use, since prion diseases are diagnosed only when neurodegeneration is already apparent, and at this stage these antibodies would be ineffective. Even worse, some antibodies can trigger neurotoxic reactions even in the absence of prion infection.

The IRB researchers used a mix of computational simulations and laboratory experiments to develop an antibody that solves both above problems starting from an extravagant but effective idea. They took a toxic antibody that can trigger prion diseases (the Ugly) and they fused it with an antibody that is not toxic but cannot protect from prion (the Good), obtaining an artificial “double” antibody (“bispecific” in scientific terms) that can cure prion disease in the laboratory even if administered when signs of neurodegeneration are already apparent (the neuroprotective).

The study, published in PLOS Pathogens and performed in collaboration with the University of Zurich, sheds new light on the mechanism responsible for prion neurotoxicity and paves the way to new therapeutic approaches against prions and other neurodegenerative diseases.

Prion diseases are caused by a protein that, due to unknown molecular causes, can transform into an infectious and toxic agent: the prion. Prion diseases can have sporadic or hereditary origin, due to DNA mutations. In Mad Cow disease, today almost totally eradicated, the human pathology is caused by ingestion of prions present in infectious animals.

Prion diseases are rare (about 400 deaths per year in Europe) and thus unattractive for pharmaceutical companies. It is therefore important that research, performed by Universities and no-profit institutions, is supported by government agencies and private benefactors.

An artificial antibody capable of protecting from prion in the laboratory even if administered when signs of the disease are already apparent. The double antibody is formed by a combination of a neurotoxic antibody (red) and a non protective one (blue). Their interaction with prion protein (grey) is shown.



















A bispecific immunotweezer prevents soluble PrP oligomers and abolishes prion toxicity
M. Bardelli, K. Frontzek, L. Simonelli, S. Hornemann, M. Pedotti, F. Mazzola, M. Carta, V. Eckhardt, R. D'Antuono, T. Virgilio, S. F. Gonzalez, A. Aguzzi, L. Varani
in PLoS Pathog (2018) vol. 14 ppe1007335