Des nano-anticorps ciblant TDP-43 pour le traitement de maladies neurodégénératives

 

Jean-Pierre Julien

Centre de recherche Université Laval Robert Giffard

 

Domaine : neurosciences, santé mentale et toxicomanies

Fonds d'innovation Pfizer-FRQS

Concours 2013-2014

A landmark in research on neurodegenerative diseases was the report in 2006 of a protein called TDP-43 as being a major component of protein aggregates in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Subsequently, Julien and colleagues made the unexpected discovery that an overproduction of TDP-43, such as detected in ALS, can drive exaggerated activation of the nuclear factor-kB (NF-kB), a key regulator of genes involved in innate immunity.

From these results, we propose to develop a novel therapeutic approach based on production of single chain antibodies, called nanobodies, against TDP-43 that will disrupt interaction between TDP-43 and NF-kB. The first objective will be to derive recombinant antibodies (nanobodies) from the mRNA of cell lines producing antibodies against TDP-43 and to test their ability to block TDP-43 binding to NF-kB. Transfection studies in cultured cells will be carried out to determine the ability of vectors encoding nanobodies to reduce the innate immune responses and inflammation. The second objective will be to produce adeno-associated virus (AAV) vectors encoding nanobodies and to test their therapeutic effects in our biophotonic transgenic mice mimicking pathological features of ALS and allowing real-time imaging of neuroinflammation. After intracerebroventricular or intrathecal injection of viral vectors, the transgenic mice will be monitored longitudinally for behavioural and pathological changes.

This project is original in concept, technically innovative and of high potential impact. It is based on the discovery of a new therapeutic target for ALS. Moreover, such nanobodies might have therapeutic applications not only for ALS but also for other disorders with TDP-43 aggregates like FTLD, Alzheimer's and Parkinson's diseases.