Correcting tau isoform ratios with a long-acting antisense oligonucleotide alleviates 4R-tauopathy phenotypes

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Tauopathies, including frontotemporal lobar degeneration (FTLD), are linked to the accumulation of 4-repeat tau (4R-tau) isoforms.
• Loss of fused in sarcoma (FUS) or splicing factor, proline- and glutamine-rich (SFPQ) has been shown to promote 4R-tau accumulation, leading to FTLD-like symptoms and neurodegeneration in mouse models.
• Current therapeutic strategies for tauopathies are limited, necessitating the development of novel approaches targeting specific tau isoforms.

Purpose of the Study:

• To develop and evaluate novel antisense oligonucleotides (ASOs) modified with 2'-O, 4'-C-ethylene-bridged nucleic acids (ENAs) for selective reduction of 4R-tau.
• To assess the efficacy of ENA-modified ASOs in correcting the 4R-tau/3R-tau ratio and ameliorating disease phenotypes in relevant preclinical models.
• To determine the pharmacokinetic profile and duration of action of ENA-modified ASOs in the brain.

Main Methods:

• Development and in vitro screening of ENA-modified ASOs, identifying EN-06 as the lead candidate.
• Intracerebroventricular (ICV) administration of EN-06 in FUS-silenced humanized tau mice and human induced pluripotent stem cell (iPSC)-derived neurons.
• Assessment of 4R/3R-tau ratio, disease phenotypes (behavioral, morphological), neurodegeneration, and drug half-life and duration of effect.

Main Results:

• EN-06 effectively reduced the 4R-tau/3R-tau ratio while maintaining total tau expression from the MAPT gene.
• ICV administration of EN-06 ameliorated disease phenotypes, including aberrant behaviors, spine dysmorphology, and neurodegeneration in mouse models and human neurons.
• EN-06 demonstrated a prolonged half-life of approximately 6 months in the brain, with therapeutic effects lasting up to 2 years, outperforming conventional MOE-modified ASOs.

Conclusions:

• ENA-modified ASOs, specifically EN-06, represent a promising therapeutic strategy for reducing pathological 4R-tau accumulation.
• This approach offers a safe and long-acting treatment option for 4R-tau-associated tauopathies by selectively targeting the disease-driving isoform.
• The sustained efficacy and favorable pharmacokinetic profile of EN-06 highlight its potential for clinical translation in treating debilitating neurodegenerative diseases.