HTT repressors comprising a zinc-finger protein transcription factor
Inventors
Carey, Galen • Chiocco, Matthew • Choi, Vivian • Felice, Brian • Froelich, Steven • KLATTE, DEBRA • Miller, Jeffrey • Paschon, David • Rebar, Edward • Zeitler, Bryan • Zhang, Lei • Zhang, H. Steve
Assignees
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Publication Number
US-12747273-B2
Publication Date
2026-09-29
Expiration Date
Abstract
Disclosed herein are HTT repressors and methods and compositions for use of these HTT repressors. Disclosed herein are methods and compositions for diagnosing, preventing and/or treating Huntington's Disease. In particular, provided herein are methods and compositions for modifying (e.g., modulating expression of) an HD HTT allele so as to prevent or treat Huntington Disease, including mHTT repressors (that repress mHTT transcripts and thus also repress mHTT protein expression).
Core Innovation
The disclosure describes engineered zinc finger protein transcription factors, including ZFP-TF 45643, that target expanded CAG repeats to selectively repress mutant huntingtin expression while largely sparing wild-type huntingtin. Reported studies evaluate effects in Huntington's disease patient-derived cells as well as in Q175 and R6/2 mouse models. Documented outcomes include reduced mutant huntingtin mRNA, soluble protein, and aggregates, alongside reported improvements in motor-function measures.
The independent claim describes a zinc finger protein transcription factor comprising four recognition helix regions, designated F1 through F4, arranged in a specified order and linked to a repression domain. The disclosure provides this engineered transcription factor for targeted genetic regulation. In the provided material, the problem stated in the patent background section is not explicitly described.
Claims Coverage
The relevant claims identify one independent claim and one inventive feature directed to a zinc finger protein transcription factor with ordered recognition helix regions.
Zinc finger protein transcription factor with ordered recognition helix regions
Claim 1 covers a zinc finger protein transcription factor comprising a zinc finger protein with recognition helix regions F1, F2, F3, and F4 arranged in the stated order, with [procedural detail omitted for safety]. Dependent claims further specify an amino acid sequence, an encoding polynucleotide, rAAV vectors with sequences encoding a nuclear localization signal or a promoter driving expression, and pharmaceutical compositions containing the polynucleotide.
The independent claim centers on a ZFP-TF defined by the order of its four recognition helix regions, while dependent claims extend coverage to specified amino acid sequences, encoding polynucleotides, rAAV vectors, and pharmaceutical compositions.
Stated Advantages
The disclosure reports selective repression of mutant huntingtin expression while largely sparing wild-type huntingtin.
Treatment is reported to reduce mutant huntingtin mRNA, soluble protein, and aggregates, with effects persisting up to 33 weeks.
The document reports improved motor-function measures in treated mouse models.
Documented Applications
Evaluation of engineered ZFP-TFs, such as ZFP-TF 45643, to reduce mutant huntingtin expression in Huntington's disease patient-derived cells.
Evaluation in Q175 and R6/2 mouse models of Huntington's disease, including assessments of motor function.
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