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-12077773-B2
Publication Date
2024-09-03
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
A plurality of recombinant adeno-associated (rAAV) vectors is provided, including a first rAAV vector and a second rAAV vector. Each vector includes defined 5′ and 3′ ITR sequences and is arranged in 5′ to 3′ order with regulatory and coding elements.
The first vector comprises a CAG promoter, a 5′ OTOF coding region comprising exons 1 to (and through) 21 of OTOF cDNA, a SD intron sequence, and an AK recombinogenic sequence. The second vector comprises an AK recombinogenic sequence, a SA intron sequence, a 3′ OTOF coding region comprising exons 22 to (and through) exon 48 of OTOF cDNA, and a polyA sequence.
The OTOF coding region is split across the two vectors, and no single vector encodes a full-length otoferlin coding sequence. The 5′ OTOF coding region is at least 80% identical to SEQ ID NO: 101 and encodes the same amino acid sequence as encoded by SEQ ID NO: 101, and the 3′ OTOF coding region is at least 80% identical to SEQ ID NO: 107 and encodes the same amino acid sequence as encoded by SEQ ID NO: 107.
The disclosed subject matter concerns active otoferlin, including a wildtype full-length otoferlin protein, and delivery into mammalian cells enables formation of an active otoferlin protein coding sequence through recombination or trans-splicing. A composition is also provided in which the first and second rAAV vectors are encapsidated by an Anc80 capsid, and the composition comprises one or more pharmaceutically acceptable carriers, diluents, or excipients.
Claims Coverage
The provided claims content includes two independent claims. The claim coverage centers on a split OTOF dual-vector rAAV system with defined ITRs, intron elements, an AK recombinogenic sequence, and sequence-identity constraints for the split OTOF coding portions, with one independent claim additionally requiring Anc80 encapsidation and a formulated composition context.
Split otoferlin coding region in dual rAAV vectors
A plurality of recombinant adeno-associated (rAAV) vectors comprising a first rAAV vector with a CAG promoter, a 5′ OTOF coding region comprising exons 1 to (and through) 21 of OTOF cDNA, a SD intron sequence, an AK recombinogenic sequence, and a 3′ ITR; and a second rAAV vector with an AK recombinogenic sequence, a SA intron sequence, a 3′ OTOF coding region comprising exons 22 to (and through) exon 48 of OTOF cDNA, a polyA sequence, and a 3′ ITR, with the 5′ and 3′ OTOF coding regions at least 80% identical to SEQ ID NOs: 101 and 107 and encoding the same amino acid sequences as those SEQ ID NOs.
Anc80-encapsidated dual-vector otoferlin composition
A composition comprising a first rAAV vector encapsidated by an Anc80 capsid and a second rAAV vector encapsidated by an Anc80 capsid, where the first rAAV vector contains the specified 5′ OTOF coding region with the SD intron and AK recombinogenic sequence and the second rAAV vector contains the specified 3′ OTOF coding region with the SA intron and polyA sequence, and the composition further comprises one or more pharmaceutically acceptable carriers, diluents, or excipients.
Across the independent claims, the core inventive coverage is directed to dual rAAV vectors that split the OTOF coding region into 5′ and 3′ portions and include specific intron and recombinogenic elements and defined vector regulatory elements so that full-length active otoferlin coding can be produced after delivery. One independent claim specifies the recombinant vector structure generally, while the other specifies a composition in which both vectors are encapsidated by Anc80 capsids and formulated with pharmaceutically acceptable carriers, diluents, or excipients.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating non-syndromic sensorineural hearing loss by administering at least two nucleic acid vectors encoding different portions of otoferlin that recombine or trans-splice to form a full-length active otoferlin coding sequence.
Intra-cochlear administration.
Synthetic perilymph solution characterized as an artificial perilymph composition.
Use in pharmaceutical compositions including pre-loaded syringes.
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