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TDP-43 targeted therapeutic approaches for ALS

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MediMabs would like to congratulate for their recent publication (Pozzi et al. 2019 JCI) and highlight the work of Dr. Julien, Dr. Gravel and Dr.Kriz groups from the CERVO brain research center of Université Laval, and is also proud of being part of this project with our modest contribution.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective degeneration of both upper and lower motor neurons. More than 90% of ALS cases show a pathological behavior of a protein called TDP-43.

TDP-43 is a DNA/RNA-binding protein that is highly and ubiquitously expressed, with main localization in the cell nucleus. The protein is a multifunctional factor with two RNA recognition domains (RRM1 and RRM2) and is involved in different aspects of RNA metabolism such as transcription, splicing, stabilization, and transport.

From the recombinant protein containing the RRM1 domain of TDP-43 , MediMabs has generated, selected, produced the E6 hybridoma cell line and sequenced the variable region. Based on this information single-chain antibodies (scFv) were produced. The scFv against RRMI was able to  block TDP-43–p65 interaction and thereby reduce NF-κB activation, and interfere with TDP-43 protein aggregation and mislocalization in the cell.

This had for effect to reduced microgliosis in a mouse model of acute neuroinflammation and mitigated cognitive impairment, motor defects,TDP-43 proteinopathy, and neuroinflammation in transgenic mice expressing ALS-linked TDP-43 mutations.

The target specificity and therapeutic effects of the scFv antibody support the feasibility of developing immunotherapeutic approaches to target intracellular TDP-43 aggregates and neuroinflammation, two hallmarks of ALS and frontotemporal dementia (FTD).

We take the occasion to reiterate Medimabs desire to help researchers in their project by providing them high quality research reagents and custom services.