Methods and compositions for modulation of tau proteins
Inventors
Riley, Brigit E. • Zeitler, Bryan
Assignees
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Publication Number
US-12318427-B2
Publication Date
2025-06-03
Expiration Date
Abstract
The present disclosure is in the field of diagnostics and therapeutics for Alzheimer's Disease.
Core Innovation
The invention relates to treating tauopathy, including Alzheimer’s disease, by repressing MAPT (microtubule-associated protein tau) expression in vivo. It provides compositions that include zinc finger protein transcription factor (ZFP-TF) repressors that bind MAPT regulatory DNA sequences and repress MAPT expression. The specification emphasizes that using multiple ZFP-TFs improves repression through synergistic repression of MAPT gene expression rather than relying on a single ZFP-TF.
The core approach uses engineered zinc finger DNA-binding domains within ZFP-TFs that bind specific DNA sequences identified as SEQ ID NO: 1 and SEQ ID NO: 2. The document describes first and second ZFP-TFs designed such that their binding to these sequences results in synergistic repression of MAPT gene expression, and specifies zinc finger region architectures with defined six zinc finger regions F1 to F6 for each ZFP-TF.
The specification also describes expressing the ZFP-TFs in vivo using polynucleotides delivered by viral vectors, including AAV vectors and AAV9. It further describes promoter choices for ZFP-TF expression, including CMV promoter and neuronal synapsin (SYN/SYN1) promoter, and linked expression using a T2A (2A peptide) to link coding sequences in a single vector.
Claims Coverage
The independent claims cover a composition that includes first and second ZFP-TFs configured to repress MAPT expression by binding to two specified MAPT DNA sequences, where combined binding results in synergistic repression. The claims further require defined six-zinc-finger DNA-binding domain architectures for each ZFP-TF.
Synergistic repression of MAPT via two ZFP-TFs binding SEQ ID NO: 1 and SEQ ID NO: 2
A composition comprising a first and a second zinc finger protein transcription factor (ZFP-TF) that repress MAPT expression, wherein the first and the second ZFP-TFs bind to SEQ ID NO: 1 and SEQ ID NO: 2, or corresponding capitalized-nucleotide variants, and wherein binding of the first and the second ZFP-TFs results in synergistic repression of MAPT gene expression.
First ZFP-TF six zinc finger domain with specified SEQ ID Nos and substitutions
The DNA-binding domain of the first ZFP-TF comprises six zinc finger regions F1 to F6 comprising specified SEQ ID Nos, and includes an R-to-Q substitution at the -5 position of F1 and F5 where specified.
Second ZFP-TF six zinc finger domain with specified SEQ ID Nos
The DNA-binding domain of the second ZFP-TF comprises six zinc finger regions F1 to F6 comprising specified SEQ ID Nos, where specified.
A composition with viral-vector provided ZFP-TFs using AAV and selected promoters
The composition includes polynucleotides provided via one or more viral vectors, where the viral vectors are AAV vectors; in dependent form the viral vectors can be AAV9, and can have CMV promoter or synapsin (SYN) promoter for expression.
Single-vector linked coding sequences for two ZFP-TFs using T2A
The coding sequences for two ZFP-TF proteins are linked in-frame using a coding sequence encoding a T2A (2A peptide), for linked expression architecture.
Overall, the claim set centers on a dual-ZFP-TF composition in which each ZFP-TF has a defined six-zinc-finger DNA-binding domain targeting two specified DNA sequences, and where the combined binding produces synergistic repression of MAPT expression. Dependent claim refinements in the provided set specify viral-vector delivery, promoter elements, and linked coding sequence expression using a T2A (2A peptide).
Stated Advantages
Synergistic repression of MAPT gene expression
Repression of MAPT expression and reduction of tau mRNA and tau protein
Reduction of CSF-tau
Reported sustained effects (specifically described as stability to about 6 months)
Documented Applications
Treatment of tauopathy, including Alzheimer’s disease
Tau reduction and evaluation in animal models and measurement of tau-related biomarkers such as CSF-tau, with assessment of potential neuroinflammation using microglial/astrocyte markers
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