TDP-43 Proteinopathy in ALS-FTD: Mechanism, Target Validation and Biomarker

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Amyotrophic Lateral Sclerosis (ALS), a fatal adult onset motor neuron disease characterized by selective loss of upper and lower motor neurons, and Fronto-Temporal Dementia (FTD), a common form of dementia characterized by a progressive deterioration in behaviour, personality and/or language, share a common disease spectrum. The neuropathology involving Transactivation response element DNA-binding protein 43 (TDP-43) occurs in nearly all cases of ALS and large proportion of FTD, neurodegenerative diseases currently without effective therapy. The overarching goals of this proposal are to clarify disease mechanism, determine a therapeutic window for a novel AAV9 gene therapy, and develop a prognostic test for ALS. By developing monoclonal antibodies designed to recognize cryptic exon encode peptides, we show that loss of TDP-43 splicing repression occurs in pre-symptomatic C9ORF72 patients. This novel finding would support the idea that loss of TDP-43 function occurs during early stage of disease. In this application, we will establish this important mechanistic insight. We hypothesize that it would be possible to develop a prognostic test for prodromal phase of ALS, a critical unmet need in the field relevant for recruitment of patients at their earliest stage of disease and for monitoring target engagement in clinical trials. Finally, emerging evidence support the idea that loss of TDP- 43 splicing repression impact on many critical pathways. In contrast to targeting each of these pathways for ALS, we hypothesize that by targeting the mechanism of TDP-43 splicing repression, it may be possible to provide benefit to patients if such therapeutic strategy can be delivered during early disease which can be determined using this new diagnostic assay of TDP-43 “cryptic” peptide. As we showed previously that our AAV9-CTR has the potential to complement the loss of TDP-43 function in ALS, we hypothesize that a window of opportunity for this gene therapy can be defined in our mouse model lacking TDP-43 in spinal motor neurons. Together, results from our proposed studies will have important implications for understanding disease mechanism, validating therapeutic strategy and developing a prognostic test for the prodromal phase of ALS.