Abstract
Background: Tau is a microtubule-stabilizing protein present in neuronal axons and is essential in the overall functioning of neurons. Tauopathy disorders, such as Alzheimer’s Disease (AD), progressive supranuclear palsy (PSP), and Corticobasal degeneration (CBD), are characterized by the accumulation and deposition of abnormal tau protein. Current therapies approved to treat these conditions have been limited to addressing symptoms instead of the underlying cause. New therapies targeting abnormal tau accumulation are currently emerging and include a variety of mechanisms that target post-translational modification, clearance, and aggregation of tau. It is important to explore these potential anti-tau therapies and their efficacy in the treatment of neurodegenerative tauopathies.
Objective: The objective of this review study is to evaluate the mechanisms that are being targeted to treat tauopathy disorders.
Methods: This review was designed to examine potential anti-tau therapies that are currently undergoing preclinical and clinical trials. The current targets that will be investigated in this study includes 1) post-translational modification involving phosphorylation, acetylation, and glycosylation of tau, 2) tau aggregation inhibitors, and 3) microtubule stabilizers. The treatments under investigation in this study is delivered mainly via 1) immunotherapy, and 2) gene therapy. Efficacy, side effects, and challenges encountered for each drug target will be reviewed.
Results: There are several clinical trials currently underway to develop tau targeting therapies. It has been found that post-translational modification, particularly phosphorylation, has shown great promise in effectively reducing abnormal tau accumulation and improving overall function in patients with neurodegenerative conditions. Kinase inhibitors, such as Nilotinib and Masitinib, are in the advanced stages of clinical trials for treating tauopathies. Various compounds targeting post-translational modifications, such as Neflamapimod, Fasudil, PD-901, BIIB-TTBKi, and T-518, have yielded successful preclinical results and warrant further clinical development due to their great therapeutic potential. Immunotherapy with monoclonal antibodies that target tau intracellularly have also demonstrated favorable results in preclinical animal models and have therefore advanced to clinical development.
Conclusion: Emerging therapies targeting tau protein are under investigation to treat tau-associated neurodegenerative diseases. Of the various targets for anti-tau therapy, post-translational phosphorylation has shown to be the most efficacious thus far. Clinical trials are currently underway to develop monoclonal antibodies targeted to intracellular tau. These disease-modifying anti-tau therapies can benefit the underlying pathology of tauopathies.
