Modulators of chromosome 9 open reading frame 72 gene expression and uses thereof
Inventors
Nabhan, Joseph F. • Pattamatta, Amrutha • Samie, Mohammad
Assignees
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Publication Number
US-12139517-B2
Publication Date
2024-11-12
Expiration Date
Abstract
The present disclosure provides compositions and methods for modulating transcription of mutant C9orf72 gene alleles in patients in need thereof, including patients having a C9orf72-related disease such as amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD).
Core Innovation
The invention relates to engineered zinc finger protein (ZFP)-based transcription modulators (ZFP-TFs) for treating amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) caused by expanded G4C2 repeats in the human C9orf72 intron 1a region. The approach uses a fusion protein in which a ZFP DNA-binding domain binds to a target site in a human C9orf72 gene and is linked to a transcription repressor domain.
The ZFP DNA-binding domain comprises six fingers (F) and recognition helix regions identified by SEQ ID NOs. The target site is selected within the C9orf72 gene, and the fusion proteins are configured for promoter-dependent and allele-dependent functional effects, including repression of mutant C9orf72 transcripts, with described selectivity relating to the C9orf72 1a region versus the C9orf72 1b region.
The repressor function is implemented by a transcription repressor domain fused to the ZFP DNA-binding domain, with embodiments including a KRAB domain. The document also describes binding and specificity support through verification and assays, and in vivo target engagement associated with reduced sense/antisense RNA and RNA foci after delivery or expressing strategies using nucleic acid constructs such as AAV vectors.
Claims Coverage
Only one independent claim is provided in the partial content (clm-00001). It includes a fusion protein architecture with a six-finger ZFP DNA-binding domain and a transcription repressor domain that binds a target site in a human C9orf72 gene, with the ZFP DNA-binding domain specified by recognition helix sequences in a single-row table, and with dependent limitations refining the repressor domain, linkage, target-binding sequences, and functional repression behavior.
ZFP-repressor fusion protein with C9orf72 binding target site
A fusion protein comprising a zinc finger protein (ZFP) DNA-binding domain and a transcription repressor domain, wherein the ZFP DNA-binding domain binds to a target site in a human C9orf72 gene.
Six-finger ZFP DNA-binding domain with specified recognition helices
The ZFP DNA-binding domain comprises six fingers (F) respectively comprising the recognition helix regions shown in a single-row table, with the SEQ ID NO of each sequence indicated in parenthesis.
ZFP DNA-binding domain binds C9orf72 with defined six-finger recognition helix sequence set
The recognition helix regions of F1-F6 are defined by the sequences listed in the table and their SEQ ID NOs.
The provided independent claim primarily covers fusion proteins combining a six-finger ZFP DNA-binding domain, defined by specific recognition-helix sequences and SEQ ID NOs, with a transcription repressor domain, where the ZFP domain binds a target site in a human C9orf72 gene. The dependent claims refine these components by specifying the repressor domain, peptide linkage, and selected recognition-helix/SEQ ID NO sets, and by constraining functional outcomes such as repression of mutant allele sense and/or antisense transcription with described promoter selectivity.
Stated Advantages
Represses mutant C9orf72 transcripts including sense and/or antisense transcription effects.
Provides promoter selectivity, including repression at the C9orf72 1a promoter with limited or no repression at the C9orf72 1b promoter.
Achieves defined quantitative repression of mutant-allele sense and/or antisense transcription by thresholds described as at least about 30% to 95%.
Documented Applications
Treatment of ALS/FTD caused by expanded G4C2 repeats in the human C9orf72 intron 1a region using engineered ZFP-based transcription modulators (ZFP-TFs).
Repression of mutant C9orf72 allele transcription, including sense and/or antisense RNA effects, with described promoter-dependent behavior relating to 1a versus 1b.
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