Methods of treating non-syndromic sensorineural hearing loss
Inventors
Simons, Emmanuel John • Ng, Robert
Assignees
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Publication Number
US-12226493-B2
Publication Date
2025-02-18
Expiration Date
Abstract
Provided herein are compositions that include at least two different nucleic acid vectors, where each of the at least two different vectors includes a coding sequence that encodes a different portion of a stereocilin protein, and the use of these compositions to treat non-syndromic sensorineural hearing loss in a subject.
Core Innovation
The invention provides a composition comprising a first nucleic acid vector and a second nucleic acid vector. The first nucleic acid vector comprises a promoter and a 5′ coding sequence of a stereocilin protein according to SEQ ID NO: 25, and the second nucleic acid vector comprises a 3′ coding sequence of a stereocilin protein according to SEQ ID NO: 28. The two vectors together provide the stereocilin protein coding portions.
The dual-vector configuration enables stereocilin gene parts to be provided by the first and second vectors. Splicing donor and splicing acceptor signal sequences are arranged with F1 phage recombinogenic regions and polyadenylation sequences so that the nucleic acids are recombined to produce a recombined nucleic acid encoding a full-length stereocilin protein.
Additional embodiments impose exon-level constraints on the stereocilin coding sequence, including coding sequences that span two adjacent exons with no intron between neighboring exons. The nucleic acid vectors can be implemented in different vector types, including AAV, adenovirus, lentivirus, retrovirus, and plasmid-based and other nucleic-acid vector formats.
Claims Coverage
The independent claim coverage centers on a dual-vector stereocilin composition in which the 5′ and 3′ stereocilin coding portions are placed on separate nucleic acid vectors. Dependent refinements further define splicing/recombination elements, exon/intron constraints, selectable viral vector formats, a kit format, and a cochlea-focused therapeutic use claim.
Dual-vector stereocilin composition with matched 5′ and 3′ coding sequences
A composition comprising a first nucleic acid vector with a promoter and a 5′ coding sequence of a stereocilin protein according to SEQ ID NO: 25, and a second nucleic acid vector with a 3′ coding sequence of a stereocilin protein according to SEQ ID NO: 28.
Splicing-and-recombination architecture for full-length stereocilin
Splicing donor and splicing acceptor signal sequences arranged with F1 phage recombinogenic regions and polyadenylation sequences, where splicing recombines the nucleic acids to produce a recombined nucleic acid encoding a full-length stereocilin protein.
Exon-spanning coding without intervening intron
At least one 5′ or 3′ coding sequence containing a nucleotide sequence spanning two neighboring exons of a stereocilin gene with no intronic sequence between them.
Viral vector selection for the nucleic acid vectors
The first and second nucleic acid vectors are viral vectors selected from adeno-associated virus (AAV), adenovirus, lentivirus, or retrovirus vectors.
Kit format for the stereocilin dual-vector composition
A kit provided that includes a composition corresponding to any one of claims 1, 9, 10, and 11.
Cochlear treatment of non-symptomatic sensorineural hearing loss
Treating non-symptomatic sensorineural hearing loss in a subject with a defective stereocilin gene by administering into the cochlea a therapeutically effective amount of a composition corresponding to claims 9, 10, or 11.
Overall, the inventive subject matter centers on a dual-vector nucleic acid composition that specifies stereocilin sequence parts at the 5′ and 3′ ends. Dependent features further define recombination/splicing elements to produce full-length stereocilin, restrict vector types, and include kit and cochlea-focused therapeutic use aspects.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating non-symptomatic sensorineural hearing loss in a subject with a defective stereocilin gene by administering into the cochlea a therapeutically effective amount of a composition corresponding to the specified claims.
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