Discovery and development of diagnostics and therapeutics for TDP-43 proteinopathies
Tamara Seredenina1, Tariq Afroz1, Vincent Darmency1, Cedric Boudou1, Jacqueline Kocher1, Mayank Chauhan1, Anthony Marchand1, Heiko Kroth1, Ajay Purohit2, David Paterson2, Laurent Martarello2, Manuela Neumann3, Jan Stoehr1, Andrea Pfeifer1, Andreas Muhs1
1AC Immune SA, Lausanne, Switzerland; 2Biogen Global Biomarker Discovery & Development, Cambridge, USA; 3Department of Neuropathology, University of Tübingen, Germany
TDP-43 is multifunctional and essential RNA-binding protein (RBP), whose cytoplasmic aggregation is the molecular basis for neurodegeneration in the majority of patients with amyotrophic lateral sclerosis (ALS) and in about 45% of patients with frontotemporal dementia (FTD). Moreover, TDP-43 copathology is also found in sub-populations of Alzheimer's disease (AD), Huntingtons' disease (HD), Lewy body diseases, Pick's disease etc1, but their contribution to disease is currently unknown. Neurodegenerative diseases linked to deposition of TDP-43 are therefore classified as TDP-43 proteinopathies. Even though the loss of normal nuclear localization and cytoplasmic TDP-43 aggregation correlates with neurodegeneration, the exact mechanisms of neurotoxicity remain elusive. Nonetheless, recent research suggests that similar to other protein aggregation diseases, TDP-43 proteinopathies follow the prion paradigm through templated conversion and spread of pathologic conformers across the central nervous system (CNS). Antibody-mediated clearance of pathological TDP-43 aggregates therefore represents an attractive strategy for therapeutic intervention. However, the lack of tools for accurate diagnosis and monitoring of disease progression have impeded the research and development of therapeutics for TDP-43 proteinopathies.
We have generated antibodies that specifically recognize pathological TDP-43 inclusions in post-mortem brain tissue from ALS and FTD patients. These antibodies display high affinity and selectivity for misfolded TDP-43 in vitro and are currently being evaluated for their therapeutic potential. To complement the therapeutic approach, we are generating small molecules suitable for further development as positron emission tomography (PET) ligands. In addition, we have identified a set of small molecules that specifically bind to pathological TDP-43 in post-mortem brain tissue and display suitable CNS PET properties. Additional compounds are currently being synthesized and evaluated with the goal to develop PET ligands with high affinity for TDP-43 while being selective over amyloid-beta and tau aggregates.