Therapeutics targeting TDP-43 to treat alzheimer's disease and related disorders - TDP-43 is a mixed proteinopapthy in alzheimer's disease (ad), ad-TDP, based on substantial epidemiological data…

Therapeutics targeting TDP-43 to treat alzheimer's disease and related disorders - TDP-43 is a mixed proteinopapthy in alzheimer's disease (ad), ad-TDP, based on substantial epidemiological data correlating TDP-43 inclusions with cognitive decline in ad patients. TDP-43 associated ad has been termed as limbic-predominant age-related TDP-43 encephalopathy (LATE) as well as other acronyms, underlying the newly-recognized importance of TDP-43 in ad (ad-TDP). Ad is the most common cause of mid- to LATE-life cognitive impairment and dementia, afflicting ~30 million people worldwide based on an extensive review of clinical and pathological studies, TDP-43 proteinopathy is associated with an amnestic dementia syndrome that occurs in older adults. A statistical analysis of attributable risk suggests that TDP-43 associated ad is a major public health issue accounting for up to 20% of cases of clinically diagnosed ad dementia. This TDP-43 proteinopathy is a distinct clinical and pathological entity from other TDP-43 associated diseases that may also be treatable with a TDP-43 targeted therapy, such as amyotrophic lateral sclerosis (ALS) and certain forms of frontotemporal lobar degeneration (FTLD-TDP). Therefore, successful completion of this project has the potential to identify TDP-43-based therapeutics for the treatment of other diseases where TDP-43 plays a major and causative role. We have discovered small molecules that bind to TDP-43 in such a way as to inhibit binding of RNA to TDP-43 and prevent TDP-43 aggregation, with activity suggestive of a therapeutic effect in three models: (1) human wild-type and mutant TDP-43 expressed in drosophila, (2) induced motor neurons (IMNS) from C9ORF72 patient-derived ipscs, and (3) mice expressing human TDP-43 (THY1 promotor). Evidence from 2-D NMR studies and computational docking analysis suggests that these inhibitors are binding to ribonucleotide recognition motif RRM2 which contains one of the amino acids involved in a critical and functionally-relevant salt bridge with RRM1. A recent pet imaging study describes a metabolic marker to potentially select ad-TDP patients for clinical trials based on ratios of FDG imaging in different regions of the brain. In this project we seek to discover, validate and develop new small- molecule inhibitors of nucleic acid binding to TDP-43 and TDP-43 aggregation inhibitors to treat ad-TDP. Aim 1 is the optimization of in vitro potency and drug-like properties of novel TDP-43 ligands including penetration into the brain and acceptable half-life and safety measures using a comprehensive battery of pharmaceutical industry-standard assays and criteria. Aim 2 involves target engagement studies using htdp-43 transfected in HEK293T cells, patient-derived induced motor neurons from ipscs, dynamic light scattering analysis of aggregation, and X-RAY crystallography of ligands bound into TDP-43. Aim 3 is evaluation in animal models of TDP-43 pathology, initially using a THY1 promoter followed by a htdp-43 based mouse model that demonstrates cognitive impairment in the absence of locomotor deficits. Aim 4 includes IND-enabling studies, scale-up synthesis, multi-species PK and rodent toxicity.