Two Different Approaches Towards Development of Therapeutics for Neurological Disorders

The research focuses on two different approaches towards drug discovery for neurodegenerative diseases Multiple Sclerosis (MS) and Amyotrophic Lateral Sclerosis (ALS). Neurodegeneration is a progressive deterioration of neural structures leading to cognitive or motor impairment. There is still no effective therapy for any of the most common neurodegenerative diseases and the available therapies only lower the rate of the disease progression or manage the symptoms. Although neurodegenerative diseases exhibit distinct clinical characteristics, they usually present aggregation of specific protein(s) along with neuroinflammation among others. The first investigated approach towards discovering therapeutics is the use of small molecules targeting the N-terminal domain of transactive response (TAR) DNA binding protein-43 (TDP-43), a critical factor in neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s disease (AD) to disrupt the aggregation of TDP-43. Targeting the N-terminal domain (NTD) of TDP-43 by in silico docking, a small molecule called nTRD022 have been discovered binding to the NTD of TDP-43 that allosterically affects the RNA binding of the protein leading to disruption of RNA binding to TDP-43 and improving the muscle strength, as an ALS related phenotype, in Drosophila fly MS models which could potentially be further developed as ALS therapeutic. The second approach focuses on developing a systematic evolution of ligands by exponential enrichment (SELEX) to generate therapeutic aptamers. Aptamers are short nucleic acid ligands that are able to specifically recognize a target with high specificity and high affinity. They have been widely used in therapeutic and diagnostic applications for neurodegenerative diseases over the last two decades. However, due to their relatively recent development, there are not as many aptamers in clinical trials as expected. In this study, aptamers have been developed against autoantibodies ta