Myosin 15 promoters and uses thereof
Inventors
Burns, Joseph • ELLIS, Kathryn • Palermo, Adam • SCHWANDER, MARTIN • WHITTON, Jonathon
Assignees
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Publication Number
US-12233136-B2
Publication Date
2025-02-25
Expiration Date
Abstract
The disclosure provides polynucleotides containing regions of the Myosin 15 (Myo15) promoter, as well as vectors containing the same, that can be used to promote expression of a transgene specifically in hair cells. The polynucleotides described herein may be operably linked to a transgene, such as a transgene encoding a therapeutic protein, so as to promote hair cell-specific expression of the transgene. The polynucleotides described herein may be operably linked to a therapeutic transgene and used for the treatment of subjects having or at risk of developing hearing loss or vestibular dysfunction.
Core Innovation
The invention concerns Myosin 15 (Myo15) promoter regions and variants that comprise upstream regulatory element sequences, including functional blocks, that are operably linked to drive hair-cell-specific transgene expression. The promoter regions and variants are defined by polynucleotide sequence identity to specified SEQ ID NOs, and include embodiments where a first region and a second region are fused directly or are joined by a linker comprising one to one hundred nucleotides.
The constructs are provided in nucleic acid form, including nucleic acid vectors such as plasmids and AAV vectors, with multiple AAV serotypes described. Hair-cell restricted reporter expression is shown using GFP, and promoter activity is described as improved versus CMV in an AAV-TMC1 context in Tmc1 knockout mice, using ABR threshold restoration as an outcome.
The invention further relates to therapeutic applications in which the Myo15 promoter constructs drive expression of therapeutic transgenes, including therapeutic proteins selected from a panel of proteins described in the document. The stated therapeutic uses include treating or preventing sensorineural hearing loss and vestibular dysfunction, addressing tinnitus, promoting hair cell regeneration or survival, and reducing ototoxic drug-induced hair cell damage.
Claims Coverage
The provided independent claim covers one inventive feature centered on a polynucleotide architecture using two sequence-defined Myo15 promoter/regulatory regions connected by direct fusion or a linker. The claim emphasizes high sequence identity thresholds and operable linkage of the first region and second region.
High-identity first and second promoter regions operably linked for fusion or linker connection
A polynucleotide comprising a first region having at least 85% sequence identity to SEQ ID NO: 1 or a functional portion thereof comprising the sequence of SEQ ID NO: 3 and/or SEQ ID NO: 4, operably linked to a second region having at least 85% sequence identity to SEQ ID NO: 2 or a functional portion thereof comprising the sequence of SEQ ID NO: 8 and/or SEQ ID NO: 9, wherein the first region is fused directly to the second region or is joined to the second region by a linker comprising one to one hundred nucleotides.
Coverage is centered on a sequence-defined Myo15 polynucleotide construct in which two promoter/regulatory regions are connected by direct fusion or a short linker, with the regions defined by high sequence identity to specified SEQ IDs or functional portions.
Stated Advantages
Promoter specificity described as hair-cell restricted GFP expression.
Improved efficacy versus CMV in an AAV-TMC1 construct in Tmc1 knockout mice, with ABR threshold restoration.
Ability to drive expression in cochlear and vestibular hair cells for treating or preventing sensorineural hearing loss and vestibular dysfunction, and for addressing tinnitus.
Promotion of hair cell regeneration or survival and reduction of ototoxic drug-induced hair cell damage.
Documented Applications
Treatment or prevention of sensorineural hearing loss.
Treatment of vestibular dysfunction including vertigo, dizziness, and imbalance.
Treatment or addressing tinnitus.
Promotion of hair cell regeneration or survival.
Reduction of ototoxic drug-induced hair cell damage.
Use of Myo15 promoter-driven constructs with in vivo and in vitro examples demonstrating hair-cell restricted GFP expression and improved efficacy versus CMV in Tmc1 knockout mice using ABR threshold restoration, including non-human primate embodiments being described.
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