Abstract Body

As a central pathological hallmark, nuclear clearance of TDP-43 accompanied by its cytoplasmic aggregates in neurons and glia have been documented in ALS-FTD and Alzheimer’s disease (AD) patients with TDP-43 pathology. As recent studies in human disease support the view that loss of TDP-43 splicing repression underlies neurodegeneration, identification of TDP-43 loss-of-function as antemortem biomarkers will be critical for clinical application.

Since incorporation of TDP-43 nonconserved cryptic exons can be seen in brains of ALS-FTD and some AD cases, it may be possible that such loss of splicing repression can be detected in biofluids of patients with TDP-43 pathology. While some nonconserved cryptic exons can be fused in frame, giving rise to putative novel epitopes within the cryptic exon-encoded peptides, it would be possible to develop specific monoclonal antisera recognizing these neo-epitopes.

We have identified a set of human nonconserved cryptic exon targets for development of a panel of antibody probes to screen biofluids from patients. We have generated and characterized a battery of monoclonal antibodies recognizing nonconserved cryptic exon-encoded neopeptides.

Identification of these antigens in biofluids would not only serve as ante-mortem biomarkers to facilitate recruitment of patients as early as possible for clinical trials, but also to demonstrate target engagement and monitor efficacy of therapeutic strategy.

Current studies are designed to validate these monoclonal antisera for detection of nonconserved cryptic exons in CSF or blood of ALS-FTD as well as AD patients exhibiting TDP-43 pathology.