Identification of TDP-43 Cryptic Exons as Functional Fluid Biomarkers for Alzheimer's Disease and Related Dementia

JHU C16735

Unmet Need: TDP-43 (Tar DNA-binding protein 43) acts as a guardian of the transcriptome by repressing the splicing of non-conserved, unannotated cryptic exons. Loss of TDP-43 function causes neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE), inclusion body myositis (IBM), and Alzheimer’s Disease (AD). Disclosed herein are antibodies and assays to detect loss of TDP-43 function in splicing repression, as a powerful tool for early disease detection and prognosis. 

Advantages disclosed herein:

• Novel antibody and assay to detect loss of function TDP-43
• Useful for early-stage, pre-symptomatic disease detection, clinical trial enrollment, and treatment monitoring of neurodegenerative diseases, including ALS, FTD, LATE and AD as well as IBM.

Technology Overview: Researchers at Johns Hopkins University have developed novel biomarkers and methods to detect neoantigens derived from dysfunctional TDP-43, useful for the detection of early-stage, pre-symptomatic neurodegenerative disease. Loss of TDP-43 splicing repression results in the inclusion of cryptic exons and production of neoantigens. Disclosed is a novel monoclonal antibody against a TDP-43-associated cryptic exon-encoded neoantigen, and ELISA-based detection assay in human fluid. Collectively, this system presents a powerful tool to detect diseases including ALS, FTD, LATE and AD as well as IBM at an early stage including before the onset of symptoms, as well as help guide and monitor patient enrollment and treatment for an improved patient outcome.   

Stage of Development: Preclinical in vivo data

Publication: https://doi.org/10.1101/2023.01.23.525202