The development of peptide- and oligonucleotide-based drugs to prevent the formation of abnormal tau in tauopathies.

INTRODUCTION: Tauopathies represent clinicopathological entities with increased and abnormal glial and/or neuronal inclusions of tau, a microtubule-binding protein. Antisense oligonucleotides (ASOs) are a promising therapeutic approach for treating tauopathies as they can target tau mRNA to reduce total human tau expression or tau exon 10 expression and 4 R tau. Additionally, targeting the tau specifically with peptides may be a unique pharmacological approach, between small molecules and proteins.

AREAS COVERED: The present review investigates the chemical basis of designing ASOs and peptides currently known to treat tauopathies. Among ASOs targeting tau expression, BIIB080 was the first to enter clinical trial development for treating mild Alzheimer's disease (AD). Furthermore, the therapeutic potential of peptide 021 (P021, Ac-DGGLAG-NH2) in tauopathies is discussed based on preclinical studies.

EXPERT OPINION: ASOs are a promising therapeutic approach for tauopathies, particularly because ASOs may suppress the expression of harmful genes and are directly delivered to the brain, showing little systemic side effects. However, whether a generalized brain tau decrease will produce positive clinical effects remains unclear. A Phase II trial of BIIB080 is ongoing in mild AD. Neurotrophic and neurogenic peptide mimetic compounds have also shown potential as treatment options for AD and other tauopathies.