Compositions and methods for treating non-age-associated hearing impairment in a human subject
Inventors
Simons, Emmanuel John • Ng, Robert
Assignees
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Publication Number
US-12305191-B2
Publication Date
2025-05-20
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 document describes recombinant adeno-associated (rAAV) vectors configured to deliver a split otoferlin gene, with the coding region divided into a 5′ OTOF coding region comprising exons 1 to 21 and a 3′ OTOF coding region comprising exons 22 to 48. Two complementary vectors together carry the complete otoferlin coding information, with defined 5′ and 3′ ITRs, a CAG promoter, splice donor and splice acceptor intron sequences, an AK recombinogenic region, and a polyA sequence.
In the first rAAV vector, the CAG promoter is linked to the 5′ OTOF coding region, followed by an SD intron sequence and the AK recombinogenic region, with the vector completed by a 3′ ITR. In the second rAAV vector, the AK recombinogenic region is followed by an SA intron sequence and then the 3′ OTOF coding region, together with a polyA sequence and a 3′ ITR, thereby defining a two-vector system for split otoferlin delivery.
The document further specifies sequence-identity constraints and defined reference sequences for the 5′ and 3′ OTOF coding regions, where the segments encode the same amino acid sequence as the referenced OTOF constructs. The composition embodiment includes a first rAAV vector and a second rAAV vector encapsidated by an Anc80 capsid and further comprises one or more pharmaceutically acceptable carriers, diluents, or excipients.
Claims Coverage
The document includes two independent claims. Across these independent claims, the inventive features focus on a split otoferlin coding region distributed between two complementary rAAV vectors, with defined ITRs, a CAG promoter, SD and SA intron sequences, an AK recombinogenic region, a polyA sequence, sequence-identity requirements, and Anc80 encapsidation in the composition claim.
Split otoferlin coding region distributed between first and second rAAV vectors
A plurality of rAAV vectors comprising a first rAAV vector having, in order from 5′ to 3′, a 5′ ITR (SEQ ID NO: 97), a CAG promoter (SEQ ID NO: 61), a 5′ OTOF coding region comprising exons 1 to 21 of OTOF cDNA with at least 90% identity to SEQ ID NO: 101 encoding the same amino acid sequence, an SD intron sequence, an AK recombinogenic region comprising SEQ ID NO: 103, and a 3′ ITR (SEQ ID NO: 104); and a second rAAV vector having, in order from 5′ to 3′, a 5′ ITR (SEQ ID NO: 97), the AK recombinogenic region (SEQ ID NO: 103), an SA intron sequence, a 3′ OTOF coding region comprising exons 22 to 48 of OTOF cDNA with at least 90% identity to SEQ ID NO: 107 encoding the same amino acid sequence, a polyA sequence, and a 3′ ITR (SEQ ID NO: 104).
Anc80-encapsidated dual-vector composition with split OTOF segments and carriers
A composition comprising a first rAAV vector and a second rAAV vector, each encapsidated by an Anc80 capsid, wherein the first rAAV vector comprises, in order from 5′ to 3′, a 5′ ITR (SEQ ID NO: 97), a CAG promoter (SEQ ID NO: 61), a 5′ OTOF coding region comprising exons 1 to 21 of OTOF cDNA with at least 95% identity to SEQ ID NO: 101 encoding the same amino acid sequence, an SD intron sequence, an AK recombinogenic region comprising SEQ ID NO: 103, and a 3′ ITR (SEQ ID NO: 104); and the second rAAV vector comprises, in order from 5′ to 3′, a 5′ ITR (SEQ ID NO: 97), the AK recombinogenic region (SEQ ID NO: 103), an SA intron sequence, a 3′ OTOF coding region comprising exons 22 to 48 of OTOF cDNA with at least 95% identity to SEQ ID NO: 107 encoding the same amino acid sequence, a polyA sequence, and a 3′ ITR (SEQ ID NO: 104), wherein the composition further comprises one or more pharmaceutically acceptable carriers, diluents, or excipients.
Both independent claims are grounded in a dual-AAV arrangement in which a split OTOF coding region is partitioned between a first vector carrying 5′ OTOF exons 1–21 and a second vector carrying 3′ OTOF exons 22–48. The first independent claim specifies a plurality of vectors with at least 90% sequence identity for each OTOF segment and a defined order of ITRs, CAG promoter, SD/SA intron elements, an AK recombinogenic region, and polyA. The second independent claim narrows the system to an Anc80-encapsidated composition with at least 95% sequence identity for each OTOF segment and includes pharmaceutically acceptable carriers, diluents, or excipients.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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