# US 2008/0187576 A1 · Methods for treating articular disease or dysfunction using self-complimentary adeno-associated viral vectors

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- Number: US 2008/0187576 A1
- Document ID: US20080187576A1
- Status: Published application
- Kind: A1
- Application number: 11/764,771
- Filed: 2007-06-18
- Published: 2008-08-07
- Earliest claimed: 2006-06-16
- Assignees: University of Florida Research Foundation, Inc.; The Brigham and Women's Hospital, Inc.
- Inventors: Steven Craig Ghivizzani; Christopher Howard Evans; Elvire Gouze; Jean-Noel Gouze
- Web page: https://patentgrep.com/patent/US20080187576A1

## CPC

- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- 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 48/0075: {characterised by an aspect of the delivery route, e.g. oral, subcutaneous}
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- C07K 14/54: Interleukins [IL]
- C12N 15/86: Viral vectors
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- C12N 2830/008: cell type or tissue specific enhancer/promoter combination
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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

Disclosed are methods and compositions for treating articular diseases such as osteoarthritis and rheumatoid arthritis, or articular dysfunction in mammals. Also disclosed are self-complimentary AAV vectors useful in gene therapy and delivery of therapeutic constructs to mammalian cells, and in particular, articular joints, cartilage, ligaments, tendons, and surrounding tissues.

## Claims

### Claim 1

A method for providing to a mammal in need thereof, a therapeutically-effective amount of a mammalian Interleukin-1 Receptor Antagonist peptide or polypeptide, said method comprising at least the step of:
(a) introducing into a plurality of cells or in a selected tissue of said mammal, a composition comprising a recombinant self-complimentary adeno-associated viral vector, wherein said vector comprises a nucleic acid segment that encodes a biologically-active mammalian IL-1Ra peptide or polypeptide, operably linked to a promoter that is capable of expressing said nucleic acid segment in a mammalian host cell that comprises said vector, in an amount, and for a time effective, to provide said mammal with said therapeutically-effective amount of said mammalian Interleukin-1 Receptor Antagonist peptide or polypeptide.

### Claim 2 (depends on 1)

The method of claim 1, wherein said mammal has, is diagnosed with, or is at risk for developing arthritis, osteoarthritis, rheumatoid arthritis, a disease of the joint, or an articular or peri-articular injury, defect or dysfunction.

### Claim 3 (depends on 1)

The method of claim 1, wherein said composition is administered to said mammal intramuscularly, intravenously, subcutaneously, intra-articularly, or peri-articularly.

### Claim 4 (depends on 3)

The method of claim 3, wherein said composition is administered to the joint, synovium, subsynovium, joint capsule, tendon, ligament, cartilage or a peri-articular muscle of said mammal.

### Claim 5 (depends on 1)

The method of claim 1, wherein said composition is directly injected into a first joint or first periarticular space of said mammal.

### Claim 6 (depends on 1)

The method of claim 1, wherein said composition is formulated for administration to a human.

### Claim 7 (depends on 6)

The method of claim 6, wherein said human is diagnosed with a joint injury, trauma, defect, disease, disorder, or dysfunction.

### Claim 8 (depends on 7)

The method of claim 7, wherein said human is diagnosed with arthritis, osteoarthritis, neuromuscular disease, autoimmune disorder, or a joint injury or defect.

### Claim 9 (depends on 1)

The method of claim 1, wherein said promoter is selected from the group consisting of a CMV promoter, a β-actin promoter, an EF1 promoter, a U1a promoter, a Tet-inducible promoter, a VP16-LexA promoter, a U1b promoter, and a joint-specific promoter.

### Claim 10 (depends on 9)

The method of claim 9, wherein said β-actin promoter is a chicken M-actin promoter.

### Claim 11 (depends on 1)

The method of claim 1, wherein said composition comprises a double-stranded adeno-associated viral particle or virion.

### Claim 12 (depends on 1)

The method of claim 1, wherein said composition comprises a plurality of adeno-associated viral particles, wherein at least one of said particles comprises a recombinant self-complimentary adeno-associated viral vector that encodes said peptide or polypeptide.

### Claim 13 (depends on 1)

The method of claim 1, wherein said composition further comprises at least a second therapeutic compound.

### Claim 14 (depends on 1)

The method of claim 1, wherein said composition further comprises a liposome, lipid carrier, lipid complex, microsphere, microparticle, nanosphere, or nanoparticle.

### Claim 15 (depends on 1)

The method of claim 1, wherein said composition is introduced into said cells or said tissue ex vivo; and further wherein said method comprises the additional step of introducing the resulting ex vivo cells or tissue that comprise said composition into at least a first tissue, joint, or peri-articular region of said mammal.

### Claim 16 (depends on 1)

The method of claim 1, wherein said nucleic acid segment encodes a biologically-active mammalian IL-1Ra peptide or polypeptide comprising an amino acid sequence that is at least about 95% identical to the polypeptide sequence of any one of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21.

### Claim 17 (depends on 16)

The method of claim 16, wherein said nucleic acid segment encodes a biologically-active mammalian IL-1Ra peptide or polypeptide comprising an amino acid sequence that is at least about 98% identical to the polypeptide sequence of any one of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, or SEQ ID NO:21.

### Claim 18 (depends on 17)

The method of claim 17, wherein said nucleic acid segment encodes a biologically-active mammalian IL-1Ra peptide or polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21.

### Claim 19 (depends on 16)

The method of claim 16, wherein said nucleic acid segment encodes a biologically-active mammalian IL-1Ra peptide or polypeptide comprising an amino acid sequence that is at least about 95% identical to the polypeptide sequence of SEQ ID NO:2.

### Claim 20 (depends on 19)

The method of claim 19, wherein said nucleic acid segment encodes a biologically-active mammalian IL-1Ra peptide or polypeptide comprising an amino acid sequence that is at least about 98% identical to the polypeptide sequence of SEQ ID NO:2.

### Claim 21 (depends on 20)

The method of claim 20, wherein said nucleic acid segment encodes a biologically-active mammalian IL-1Ra peptide or polypeptide comprising the amino acid sequence of SEQ ID NO:2.

### Claim 22 (depends on 16)

The method of claim 16, wherein said nucleic acid segment comprises a nucleotide sequence that is at least about 95% identical to the polynucleotide sequence of SEQ ID NO: 1.

### Claim 23 (depends on 22)

The method of claim 22, wherein said nucleic acid segment comprises a nucleotide sequence that is at least about 98% identical to the polynucleotide sequence of SEQ ID NO: 1.

### Claim 24

A method for providing directly to a mammalian joint or periarticular space, a therapeutically-effective amount of a biologically-active IL-1Ra peptide or polypeptide, said method comprising directly injecting into at least a first joint or periarticular space of said mammal an effective amount of a composition comprising:
a recombinant self-complimentary adeno-associated viral vector that comprises a nucleic acid segment that encodes a biologically-active mammalian IL-1Ra peptide or polypeptide, operably linked to a promoter that is capable of expressing said nucleic acid segment in a mammalian host cell that comprises said vector, in an amount, and for a time effective, to directly provide to said mammalian joint or periarticular space, said therapeutically-effective amount of said mammalian Interleukin-1 Receptor Antagonist peptide or polypeptide.

### Claim 25

A method for treating or ameliorating the symptoms of an articular defect, injury, disease or dysfunction in a mammal, said method comprising administering to said mammal a composition comprising: recombinant self-complimentary adeno-associated viral vector that comprises a nucleic acid segment encoding a biologically-active mammalian IL-1Ra peptide or polypeptide, said segment operably linked to at least a first promoter that is capable of expressing said nucleic acid segment in a mammalian host cell that comprises said vector; in an amount and for a time sufficient to treat or ameliorate the symptoms of said articular defect, injury, disease or dysfunction in said mammal.