Development of therapeutic strategies
Development of methods to detect prions in human and animal biological fluids & organs
- P.I. Adriano Aguzzi, Institute of Neuropathology, University Hospital Zürich, Switzerland
- Paolo Dametto, Institute of Neuropathology, University Hospital Zürich, Switzerland
- Simone Hornemann, Institute of Neuropathology, University Hospital Zürich, Switzerland
2010: 1 year / Grant: 40 000 euros
Project: The project named “UltraMab” proposed to develop new anti-PrP antibodies of high purity
and affinity. The idea was to derive the antibodies from hybridoma devoid of cellular PrP to avoid
any antibody neutralization. The team also planed to use these antibodiesfor the treatment of prion
diseases. As antibodies could be toxic because of the occurrence of an immunological reaction, the
antibody parts that interact with the immune system could be removed.
Main results and related published data: Following the production of new antibodies that
appeared to detect PrPC and PrPTSE well, some of them were tested for therapeutic purposes and
were shown to be toxic. Additional experiments determined that the flexible tail of PrPC wasrequired
to transmit toxic signals that originate from the globular domain when this one interacts with antiPrP
antibodies. Moreover, recent data showed that POM1 antibody, which targetsthe globular domain
of PrPC, triggered a neurotoxic syndrome reminiscent to prion disorders in the absence of prion
- Prion pathogenesis is faithfully reproduced in cerebellar organotypic slice cultures.Falsig
J, Sonati T, Herrmann US, Saban D, Li B, Arroyo K, Ballmer B, Liberski PP, Aguzzi A. PLoS Pathog.
2012;8(11):e1002985. doi: 10.1371/journal.ppat.1002985. Epub 2012 Nov 1.
- The toxicity of antiprion antibodies is mediated by the flexible tail of the prionprotein.
Sonati T, Reimann RR, Falsig J, Baral PK, O’Connor T, Hornemann S, Yaganoglu S, Li B, Herrmann
US, Wieland B, Swayampakula M, Rahman MH, Das D, Kav N, Riek R,Liberski PP, James MN, Aguzzi
A. Nature. 2013 Sep 5;501(7465):102-6. doi: 10.1038/nature12402. Epub 2013 Jul 31.
- The role of the NADPH oxidase NOX2 in prion pathogenesis. Sorce S, Nuvolone M, Keller A,
Falsig J, Varol A, Schwarz P, Bieri M, Budka H, Aguzzi A. PLoS Pathog. 2014 Dec 11;10(12):e1004531.
doi: 10.1371/journal.ppat.1004531. eCollection 2014.
- Prion infections and anti-PrP antibodies trigger converging neurotoxic pathways.
Herrmann US, Sonati T, Falsig J, Reimann RR, Dametto P, O’Connor T, Li B, Lau A, Hornemann S,
Sorce S1, Wagner U, Sanoudou D, Aguzzi A. PLoS Pathog. 2015 Feb 24;11(2):e1004662.:
0.1371/journal.ppat.1004662. eCollection 2015.
- Differential Toxicity of Antibodies to the Prion Protein. Reimann RR, Sonati T, Hornemann S,
Herrmann US, Arand M, Hawke S, Aguzzi A. PLoS Pathog. 2016 Jan 28;12(1):e1005401. doi: 10.1371/journal.ppat.1005401. eCollection 2016.
- Neurotoxic Antibodies against the Prion Protein Do Not Trigger PrionReplication.Frontzek
K, Pfammatter M, Sorce S, Senatore A, Schwarz P, Moos R, Frauenknecht K, Hornemann S, Aguzzi . PLoS One. 2016 Sep 29;11(9):e0163601. doi: 10.1371/journal.pone.0163601.