Frontotemporal dementia (FTD) and motor neuron disease (MND) are rapidly progressing neurodegenerative diseases with no effective treatments. They are part of a disease continuum and share a neuropathology with cytoplasmic aggregates of the nuclear TAR DNA-binding protein 43 (TDP-43) found in in >90% of MND and ~50% of FTD cases. The molecular mechanisms that drive TDP-43 mis-localization and pathology remain elusive. Using an unbiased approach, we have identified a novel interactor of TDP-43 that predominantly binds to pathogenic variants of TDP-43 and regulates their sub-cellular distribution in cellular models. Here we will use adenoassociated virus (AAV) gene delivery and CRISPR genome-edited mice to determine the pathogenic role of this novel TDP-43 interaction in different TDP-43 transgenic mouse models. We have previously shown that experimentally removing TDP-43 from symptomatic FTD/MND mice rapidly improves deficits and neuropathology. Harnessing the preferential affinity of this new interactor for pathological TDP-43, we have generated proof-ofconcept data for an AAV-based gene therapeutic approach to target pathological TDP-43. Here, we will do comprehensive efficacy and toxicity testing in different animal models. Finally, based on our previous work, we will design an alternative therapeutic approach by combing the specific motif that mediated the interaction with TDP-43 and targeted protein degradation technology known as PROTAC, and then test it in pre-clinical models in this proposal. Taken together, this research will use an innovative experimental approaches and technologies to obtain a novel insight into the pathogenesis of FTD and MND and develop alternative novel therapeutic strategies towards translation.
|Effective start/end date||1/01/21 → 31/12/23|