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-12071627-B2
Publication Date
2024-08-27
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 plurality of AAV vectors that together are capable of constituting a full-length otoferlin messenger RNA from split gene portions. A first AAV vector and a second AAV vector each comprise 5 and 3 inverted terminal repeats and collectively reconstruct the otoferlin messenger RNA in vivo. The gene encoding an otoferlin polypeptide is divided between the first and second AAV vectors, with the first vector including a promoter operably linked to a portion of the gene and the second vector including a complementary portion of the otoferlin gene.
The first and second AAV vectors comprise an F1 phage recombinogenic region, enabling formation of a full-length otoferlin messenger RNA. In related embodiments, the first vector includes a splicing donor signal sequence and the second vector includes a splicing acceptor signal sequence, with a polyadenylation signal in the second vector. The disclosed constructs keep each vector at up to about 5 kb nucleotides, including a 77 base pair F1 phage recombinogenic region in one framework.
Claims Coverage
The consolidated claim coverage identifies two independent claims. Both define a two-vector AAV system for constituting full-length otoferlin messenger RNA using an F1 phage recombinogenic region and a total nucleotide limit of up to about 5 kb per vector.
Two AAV vectors enabling full-length otoferlin mRNA reconstitution
A first AAV vector comprising 5 and 3 ITRs and a promoter operably linked to a portion of a gene encoding an otoferlin polypeptide, and a second AAV vector comprising 5 and 3 ITRs and a portion of the gene encoding an otoferlin polypeptide.
F1 phage recombinogenic region for full-length otoferlin messenger RNA
The first and second AAV vectors comprise a F1 phage recombinogenic region and are capable of constituting a full-length otoferlin messenger RNA.
Total nucleotide count limited to about 5 kb per AAV vector
The first and second AAV vectors each include a total number of nucleotides of up to about 5 kb.
Splicing donor and acceptor signal sequences with polyadenylation signal
A first AAV vector comprising a promoter, a portion of a gene encoding an otoferlin polypeptide, a splicing donor signal sequence, and 5 and 3 ITRs; and a second AAV vector comprising a splicing acceptor signal sequence, a portion of the gene encoding an otoferlin polypeptide, a polyadenylation signal, and 5 and 3 ITRs.
77 base pair F1 phage recombinogenic region
The first and second AAV vectors comprise a 77 base pair F1 phage recombinogenic region and are capable of constituting a full-length otoferlin messenger RNA.
Across the independent claims, the coverage centers on a two-vector AAV approach that uses an F1 phage recombinogenic region to constitute full-length otoferlin messenger RNA from split otoferlin gene portions. One independent claim additionally specifies splicing donor and acceptor signal sequences and a 77 base pair F1 phage recombinogenic region, with both claims limiting each vector to up to about 5 kb.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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