Htt repressors and uses thereof
Inventors
Froelich, Steven • Miller, Jeffrey C. • Paschon, David • Rebar, Edward J. • Zeitler, Bryan • Zhang, H. Steve
Assignees
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Publication Number
US-12551575-B2
Publication Date
2026-02-17
Expiration Date
Abstract
Disclosed herein are Htt repressors and methods and compositions for use of these Htt repressors.
Core Innovation
The disclosed approach uses AAV9 vectors encoding Htt repressors that comprise a KRAB repression domain and a five-domain zinc finger transcription factor to inhibit expression of mutant Htt with expanded CAG repeats. The repressors selectively target expanded CAG repeats to reduce mutant Htt expression while wild-type Htt remains largely unchanged. The claims cover specified zinc finger recognition-helix configurations, including ZFP 45643 and ZFP 46025, for in vitro cellular modulation and human symptom treatment.
Evaluations in Huntington’s Disease neurons and Q50 mice demonstrate sustained reduction of mutant Htt expression, reduced apoptosis, and increased neuronal ATP levels. Nonhuman primate studies show vector distribution beyond the infusion volume along with bidirectional axonal transport across distal brain regions. The background section is omitted from the provided material, so the specific technical problem identified there is not explicitly described in patent.
Claims Coverage
The independent claims encompass two inventive features directed to methods using AAV9 vectors encoding zinc finger protein transcription factor repressors that comprise a KRAB repression domain and five zinc finger domains.
Modifying mutant Htt expression in a cell
The claim covers modifying expression of a mutant Htt gene with at least 35 expanded CAG repeats in a mouse or human cell in vitro by administering AAV9 vector(s) encoding Htt repressors comprising a KRAB repression domain and a five-domain zinc finger protein transcription factor with specified recognition-helix sequences.
Inhibiting mutant Htt expression and treating a Huntington’s Disease symptom
The claim covers inhibiting expression of a mutant Htt gene with at least 35 expanded CAG repeats and treating a Huntington’s Disease symptom in a human subject by administering an AAV9 vector to the striatum encoding Htt repressor(s) comprising a KRAB repression domain and a five-domain zinc finger protein transcription factor with specified recognition-helix sequences.
The independent claims cover in vitro modification of mutant Htt expression in cells and treatment of Huntington’s Disease symptoms in a human subject via striatal administration of AAV9 vectors encoding specified five-domain zinc finger repressors.
Stated Advantages
The reported repression is selective for mutant Htt, with wild-type Htt remaining unchanged or largely spared.
Neuronal studies report reduced apoptosis and increased ATP in treated Huntington’s Disease neurons.
No overt toxicity is reported in the described mouse study.
Studies in nonhuman primates report AAV9 vector distribution beyond the infusion volume and bidirectional axonal transport to distal brain regions.
Documented Applications
Modifying mutant Htt expression in mouse or human cells in vitro.
Treating a symptom of Huntington’s Disease in a human subject through striatal administration and inhibition of mutant Htt expression.
Evaluation of mutant Htt repression in Q50 mice and Huntington’s Disease neurons.
Prospective human efficacy assessments and MRI-guided AAV9 delivery to the putamen.
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