Polyglutamine-expanded ataxin-3: a target engagement marker for spinocerebellar ataxia type 3 in peripheral blood

Background: Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of...

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Detalles Bibliográficos
Autores: Hübener-Schmid, Jeannette, Kuhlbrodt, Kirsten, Peladan, Julien, Faber, Jennifer, Santana, Magda M., Hengel, Holger, Jacobi, Heike, Reetz, Kathrin, Garcia-Moreno, Hector, Raposo, Mafalda, Gaalen, Judith van, Infante Ceberio, Jon|||0000-0003-4025-4606, Steiner, Katharina M., Vries, Jeroen de, Verbeek, Marcel M., Giunti, Paola, Almeida, Luis Pereira de, Lima, Manuela, Warrenburg, Bart van de, Schöls, Ludger
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/24039
Acceso en línea:http://hdl.handle.net/10902/24039
Access Level:acceso abierto
Palabra clave:Ataxin-3
Machado-Joseph disease
Spinocerebellar ataxia type 3
Singulex technology
Target engagement biomarker
Descripción
Sumario:Background: Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers. Objective: We aimed at developing an ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid (CSF). Methods: Using the novel single molecule counting ataxin-3 immunoassay, we analyzed cross-sectional and longitudinal patient biomaterials. Results: Statistical analyses revealed a correlation with clinical parameters and a stability of polyQ-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phases. Conclusions: The novel immunoassay is able to quantify polyQ-expanded ataxin-3 in plasma and CSF, whereas ataxin-3 levels in plasma correlate with disease severity. Longitudinal analyses demonstrated a high stability of polyQ-expanded ataxin-3 over a short period.

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