Methods and compositions for treating Huntington's Disease
Inventors
Miller, Jeffrey C. • Rebar, Edward J. • Zhang, H. Steve
Assignees
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Publication Number
US-11723952-B2
Publication Date
2023-08-15
Expiration Date
Abstract
Disclosed herein are compositions comprising non-naturally occurring zinc finger domains, fusion proteins comprising these zinc finger domains, polynucleotides encoding these proteins, cells expressing these proteins and pharmaceutical compositions comprising these proteins or polynucleotides as well as methods of modifying an Htt gene using these compositions for treating or preventing Huntington's Disease.
Core Innovation
The disclosure describes mRNAs encoding fusion proteins comprising a transcriptional repression domain and a non-naturally occurring zinc finger protein comprising five or six zinc finger domains. Designated zinc finger proteins specifically bind the mutant Huntington's gene allele, with dependent claims identifying sequences within the CAG repeat region as a binding location. The disclosure presents CAG-length-dependent binding as a basis for preferential repression of expanded mutant alleles.
Reported studies demonstrate selective mutant Huntingtin repression while largely sparing the normal allele in patient-derived fibroblasts, neural stem cells, and differentiated neurons. Disclosed embodiments also show reduced mutant transgene expression in R6/2 mouse striata alongside few off-target expression changes in genome-wide analysis. Embodiments encompass therapeutic compositions and methods for Huntington's Disease, alongside broader Htt-modulation and genome-editing applications.
Claims Coverage
The provided claims identify one independent claim comprising one inventive feature directed to an mRNA encoding a transcriptional repression fusion protein.
mRNA encoding a mutant Huntington's allele-binding transcriptional repression fusion protein
An mRNA encoding a fusion protein comprising a transcriptional repression domain and a non-naturally occurring zinc finger protein comprising five or six zinc finger domains, selected from designated proteins (33074, 30080, 30643, 30648, 30645, 30640, 30642, or 30646), that specifically binds to the mutant Huntington's gene allele. Dependent claims further specify binding within the CAG repeat region, host cells, pharmaceutical compositions, modification of mHtt gene expression, and treatment of Huntington's Disease.
The independent claim covers an mRNA encoding a designated zinc finger protein and transcriptional repression domain fusion that binds the mutant Huntington's gene allele, with dependent claims covering associated compositions, expression-modification methods, and therapeutic treatments.
Stated Advantages
CAG-length-dependent binding enables selective reduction of mutant HTT expression while largely sparing the normal allele.
Reported studies describe selective mHtt repression in patient-derived fibroblasts, neural stem cells, and differentiated neurons, as well as reduced mutant Htt transgene expression in R6/2 mouse striata.
Genome-wide analysis reports few off-target expression changes.
Documented Applications
Therapeutic compositions and methods for treating Huntington's Disease, including administering the claimed mRNAs to a subject.
Administration of the claimed mRNAs to a subject's striatum.
Modifying mHtt gene expression in a cell using polynucleotides encoding the claimed mRNAs.
Broader Htt-modulation and genome-editing embodiments.
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