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Joaquín Castilla, PhD

Grant Title: Exploring the efficacy of dominant negative protein-based gene therapy for different prion diseases: in vivo proof-of-concept study Location: Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain

Grant Year: 2024

Reducing the amount of prion protein in the brain of patients at risk or suffering a prion disease is one of the most promising strategies for their treatment, since it would eliminate the source required for prion multiplication and spreading. However, reducing the amount of a protein with unknown function could lead to unexpected side effects, which despite not being easily noticeable in animal models of disease, may influence the quality of life of patients under treatment. For this reason, we propose a new therapy based on the introduction of an especial prion protein called dominant negative (DN). These proteins, designed after the analysis of hundreds of different prion protein variants from distinct mammal species, are able to perform the normal functions of a prion protein, but are unable to misfold and become pathogenic and can also interfere with the harmful effects of the already misfolded proteins, hindering their multiplication and spreading throughout the brain.

After the selection of few prion protein candidates that have shown DN capacity in the test tube, in this project, we intend to test if the production of these DN proteins, could indeed delay or stop disease progression animals. For that, these special proteins will be produced directly in the brains of the animal models, successfully driven by harmless adeno-associated viruses (AAVs), an increasingly popular system for genetic therapies. First, we will determine if these DN proteins are produced in the right amounts and locations in the brain. Once correct production is confirmed, we will evaluate the effectiveness of this treatment in our fast disease-developing animal models by comparing survival rates and disease progression with mice that do not produce these DN proteins.

About the Researcher:

Joaquín Castilla joined CIC bioGUNE ( as a senior investigator in 2009, awarded an IKERBasque Research Professor position and has been since then the Principal Investigator of the Prion Research Laboratory at said institution. He has a long-lasting experience on prions, starting his work on them in 1998 at the National Center for Animal Health (CISA-INIA) in Madrid.

In 2003, he moved to Switzerland to work as Research Scientist at Serono Research Institute on the same topic and shortly after, he became Assistant Professor, first at the University of Texas, Medical Branch (2003-2006) and later at Scripps-Florida (2006-2009) leading an independent group.

His main field of expertise is the in vitro and in vivo propagation of prions. More specifically, his group focuses on studying the spontaneous misfolding of prions and the strain and species barrier phenomena in cell-free systems, trying to dissect the molecular mechanisms by which prions form and propagate, with the ultimate aim of developing new diagnostic methods and anti-prion therapeutic approaches. In order to get said achievements, Dr. Castilla has extensive experience participating in European Community, NIH (USA), and national projects. His group has over 20 active collaborations both in Europe and outside the European Union with the most prestigious groups in the prion field.

He is a member of the Journals Veterinary Research, Pathogens, and Biomolecules editorial boards and acts as a reviewer for dozens of international journals as The EMBO J., Neuron, Nature, among others. He received the Award of Young Scientific in Virology (Spanish Society of Virology) in 2011 and the Research Award of the Colegio de Médicos de Álava in 2018. He is highly involved in the Spanish Foundation for Prion diseases (, currently acting as President. Dr. Castilla has published 120 peer-reviewed articles, many of them instrumental for understanding the molecular mechanisms of prion propagation.

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