Compositions and methods for treating non-age-associated hearing impairment in a human subject
Inventors
Simons, Emmanuel John • Reisinger, Ellen • KÜGLER, Sebastian • Al-Moyed, Hanan
Assignees
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Publication Number
US-12264317-B2
Publication Date
2025-04-01
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 an otoferlin protein, and the use of these compositions to treat hearing loss in a subject.
Core Innovation
The invention relates to a method of treating otoferlin related hearing loss in a subject by administering a plurality of AAV vectors capable of constituting a full-length otoferlin messenger RNA in the subject. The hearing loss is associated with reduced expression, lack of expression, or dysfunction of otoferlin.
The plurality includes a first AAV vector and a second AAV vector, each constructed with 5′ and 3′ inverted terminal repeats (ITRs), and the vectors together provide full-length otoferlin messenger RNA expression. The invention uses a split otoferlin gene configuration across two AAV vectors with a F1 phage recombinogenic region and portions of a gene encoding an otoferlin polypeptide so that full-length otoferlin messenger RNA can be constituted in the subject.
The invention includes particular configurations of gene portions and functional genetic elements to support full-length otoferlin messenger RNA formation, including incorporation of a promoter and splicing-related signals distributed between the first and second AAV vectors. The vectors are constrained so that each includes a total number of nucleotides of up to about 5 kb, and the compositions are formulated for intracochlear administration, including embodiments using synthetic perilymph.
Claims Coverage
The document provides two independent claims centered on a dual-AAV method for treating otoferlin related hearing loss by constituting a full-length otoferlin messenger RNA in the subject. Across the independent claims, five inventive features are identified: the dual AAV configuration, the defined ITR and F1 phage recombinogenic region architecture, the splicing donor/acceptor signals in one claim, the per-vector nucleotide limit of up to about 5 kb, and the target hearing loss associated with reduced expression, lack of expression, or dysfunction of otoferlin.
Dual AAV vectors constituting full-length otoferlin messenger RNA
Administering to the subject a plurality of AAV vectors comprising a first AAV vector and a second AAV vector, wherein the first and second AAV vectors are capable of constituting a full-length otoferlin messenger RNA in the subject.
Configured AAV vector architecture with ITRs and F1 phage recombinogenic region
Each of the first and second AAV vectors includes a 5′ inverted terminal repeat (ITR), a 3′ ITR, and a F1 phage recombinogenic region, with the first vector including a promoter operably linked to a portion of a gene encoding an otoferlin polypeptide and the second vector including a portion of the gene encoding an otoferlin polypeptide.
Splicing donor and acceptor signals with a 77 base pair F1 phage recombinogenic region
A method of treating otoferlin related hearing loss by administering a plurality of AAV vectors comprising a first AAV vector with a promoter, splicing donor signal sequence, and a 77 base pair F1 phage recombinogenic region, and a second AAV vector with a splicing acceptor signal sequence and a 77 base pair F1 phage recombinogenic region, wherein the first and second AAV vectors are capable of constituting a full-length otoferlin messenger RNA in the subject.
Vector nucleotide size limit
Each of the first and second AAV vectors includes a total number of nucleotides of up to about 5 kb.
Treating hearing loss associated with reduced expression, lack of expression, or dysfunction of otoferlin
The otoferlin related hearing loss is associated with reduced expression, lack of expression, or dysfunction of otoferlin.
Overall, the independent claims center on a two-vector AAV strategy with defined vector components and split gene portions that together constitute full-length otoferlin messenger RNA in the subject, constrained by a per-vector nucleotide limit and targeted to hearing loss associated with reduced expression, lack of expression, or dysfunction of otoferlin.
Stated Advantages
Documented Applications
Treating otoferlin related hearing loss in a subject by administering a plurality of AAV vectors as defined in the claims.
Intracochlear administration of a composition that includes the plurality of AAV vectors and a synthetic perilymph solution.
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