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US 12,673,116 B2Granted
Compositions and methods for treating non-age-associated hearing impairment in a human subject
AssigneeAkouos, Inc.
InventorsEmmanuel John Simons, Robert Ng, Ellen Reisinger, Hanan Al-Moyed, Sebastian Kügler
Life of this patent
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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.
Claims8
A composition comprising a first adeno-associated virus (AAV) vector and a second AAV vector, wherein:
- a) the first AAV vector comprises a promoter, a first coding sequence that encodes an N-terminal portion of an otoferlin polypeptide positioned 3′ of the promoter, a splicing donor signal sequence positioned at the 3′ end of the first coding sequence, and a coding sequence encoding a destabilization domain, wherein the destabilization domain is 3′ to the first coding sequence and 3′ to the splicing donor signal sequence;
- and
- b) the second AAV vector comprises a splicing acceptor signal sequence, a second coding sequence that encodes a C-terminal portion of the otoferlin polypeptide positioned at the 3′ end of the splicing acceptor signal sequence, and a polyadenylation sequence at the 3′ end of the second coding sequence;
- wherein the first and/or second AAV vector comprises a stuffer sequence comprising the full-length nucleotide sequence set forth in any one of SEQ ID NOs:
- 54-58, 90 and 91, wherein the stuffer sequence is 5′ to the promoter or 3′ to the polyadenylation sequence;
- wherein when introduced into amammalian cell the first and second AAV vectors undergo intermolecular concatamerization and trans-splicing, thereby forming a recombined nucleic acid that encodes a full-length otoferlin polypeptide.
3 more elements
A plurality of adeno-associated virus (AAV) vectors comprising a first AAV vector and a second AAV vector, wherein:
- a) the first AAV vector comprises a promoter, a first coding sequence that encodes an N-terminal portion of an otoferlin polypeptide positioned 3′ of the promoter, a splicing donor signal sequence positioned at the 3′ end of the first coding sequence, and a coding sequence encoding a destabilization domain, wherein the destabilization domain is 3′ to the first coding sequence and 3′ to the splicing donor signal sequence;
- and
- b) the second AAV vector comprises a splicing acceptor signal sequence, a second coding sequence that encodes a C-terminal portion of the otoferlin polypeptide positioned at the 3′ end of the splicing acceptor signal sequence, and a polyadenylation sequence at the 3′ end of the second coding sequence;
- wherein the first and/or second AAV vector comprises a stuffer sequence comprising the full-length nucleotide sequence set forth in any one of SEQ ID NOs:
- 54-58, 90 and 91, wherein the stuffer sequence is 5′ to the promoter or 3′ to the polyadenylation sequence;
- wherein when introduced into amammalian cell the first and second AAV vectors undergo intermolecular concatamerization and trans-splicing, thereby forming a recombined nucleic acid that encodes a full-length otoferlin polypeptide.
3 more elements
Dependencies are inferred from the claim text.