# US 11,660,353 B2 · Compositions and methods for treating sensorineural hearing loss using otoferlin dual vector systems

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- Number: US 11,660,353 B2
- Document ID: US11660353B2
- Status: Granted
- Kind: B2
- Application number: 16/395,999
- Filed: 2019-04-26
- Published: 2020-05-21
- Granted: 2023-05-30
- Earliest claimed: 2018-04-27
- Assignees: Decibel Therapeutics, Inc.
- Applicants: Decibel Therapeutics, Inc.
- Inventors: Joseph Burns; Kathryn Ellis; Adam Palermo; Martin Schwander; Jonathon Whitton
- Web page: https://patentgrep.com/patent/US11660353B2

## CPC

- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- C07K 14/50: Fibroblast growth factor [FGF]
- A61K 48/0075: {characterised by an aspect of the delivery route, e.g. oral, subcutaneous}
- C07K 14/47: from mammals
- C12N 15/86: Viral vectors
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0046: {Ear}
- A61K 9/0048: {Eye, e.g. artificial tears}
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- C12N 2750/14144: Chimeric viral vector comprising heterologous viral elements for production of another viral vector
- C12N 2840/007: cell or tissue specific
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The disclosure features compositions and methods for the treatment of sensorineural hearing loss and auditory neuropathy, particularly forms of the disease that are associated with mutations in otoferlin (OTOF), by way of OTOF gene therapy. The disclosure provides a variety of compositions that include a first nucleic acid vector that contains a polynucleotide encoding an N-terminal portion of an OTOF protein and a second nucleic acid vector that contains a polynucleotide encoding a C-terminal portion of an OTOF protein. These vectors can be used to increase the expression of OTOF in a subject, such as a human subject suffering from sensorineural hearing loss.

## Claims

### Claim 1

A composition comprising:
a first nucleic acid vector comprising a myosin 15 (Myo15) promoter having at least 98% sequence identity to the sequence of SEQ ID NO: 36 operably linked to a first coding polynucleotide that encodes an N-terminal portion of an otoferlin (OTOF) protein; and
a second nucleic acid vector comprising a second coding polynucleotide that encodes a C-terminal portion of an OTOF protein and a polyadenylation (poly(A)) sequence positioned at a 3′ end of the second coding polynucleotide,
wherein neither the first nor second nucleic acid vector encodes a full-length OTOF protein, and, when introduced into a mammalian cell, the first and second nucleic acid vectors undergo homologous recombination or concatemerization to form a recombined nucleic acid that encodes a full-length OTOF protein.

### Claim 2 (depends on 1)

The composition of claim 1, wherein
the first nucleic acid vector further comprises a splice donor signal sequence positioned at a 3 ′ end of the first coding polynucleotide; and
the second nucleic acid vector further comprises a splice acceptor signal sequence, wherein the second coding polynucleotide that encodes a C-terminal portion of an OTOF protein is positioned at a 3′ end of the splice acceptor signal sequence,
wherein the first coding polynucleotide and the second coding polynucleotide do not overlap.

### Claim 3 (depends on 1)

The composition of claim 1, wherein
the first nucleic acid vector further comprises a splice donor signal sequence positioned at a 3′ end of the first coding polynucleotide and a first recombinogenic region positioned 3′ of the splice donor signal sequence; and
the second nucleic acid vector further comprises a second recombinogenic region and a splice acceptor signal sequence positioned 3′ of the second recombinogenic region, wherein the second coding polynucleotide that encodes a C-terminal portion of an OTOF protein is positioned at a 3′ end of the splice acceptor signal sequence,
wherein the first coding polynucleotide and the second coding polynucleotide do not overlap.

### Claim 4 (depends on 3)

The composition of claim 3, wherein the first and second recombinogenic regions have the same nucleic acid sequence.

### Claim 5 (depends on 3)

The composition of claim 3, wherein the first nucleic acid vector further comprises a degradation signal sequence positioned 3′ of the recombinogenic region; and wherein the second nucleic acid vector further comprises a degradation signal sequence positioned between the recombinogenic region and the splice acceptor signal sequence.

### Claim 6 (depends on 2)

The composition of claim 2, wherein the division between the first and second coding polynucleotides is at an OTOF exon boundary.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the first and second nucleic acid vectors are adeno-associated virus (AAV) vectors.

### Claim 8 (depends on 1)

The composition of claim 1, wherein the first and second coding polynucleotides that encode the OTOF protein do not comprise introns.

### Claim 9 (depends on 1)

The composition of claim 1, wherein the first and second nucleic acid vectors comprise an inverted terminal repeat (ITR) at each end of the nucleic acid sequence.

### Claim 10 (depends on 1)

The composition of claim 1, wherein the second nucleic acid vector comprises a Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element (WPRE).

### Claim 11 (depends on 1)

The composition of claim 1, wherein the Myo15 promoter comprises the sequence of SEQ ID NO: 36.