# US 9,433,688 B2 · Method of treating or retarding the development of blindness

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- Number: US 9,433,688 B2
- Document ID: US9433688B2
- Status: Granted
- Kind: B2
- Application number: 14/310,015
- Filed: 2014-06-20
- Published: 2014-12-25
- Granted: 2016-09-06
- Earliest claimed: 2001-04-13
- Assignees: The Trustees of the University of Pennsylvania; University of Florida Research Foundation, Inc.; Cornell Research Foundation, Inc.
- Applicants: The Trustees of the University of Pennsylvania; University of Florida Research Foundation, Incorporated; Cornell Research Foundation, Inc.
- Inventors: Gregory M. Acland; Gustavo D. Aguirre; Jean Bennett; William W. Hauswirth; Samuel G. Jacobson; Albert M. Maguire
- Web page: https://patentgrep.com/patent/US9433688B2

## CPC

- A61K 48/0058: {Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 31/70: Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K31/047)
- A61K 38/465: {acting on ester bonds (3.1), e.g. lipases, ribonucleases}
- A61K 38/51: Lyases (4)
- A61K 38/52: Isomerases (5)
- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- A61K 48/0075: {characterised by an aspect of the delivery route, e.g. oral, subcutaneous}
- A61P 27/02: Ophthalmic agents
- C07K 14/705: Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)}
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- C12N 15/86: Viral vectors
- C12N 15/8645: {Adeno-associated virus}
- C12Y 301/01064: Retinoid isomerohydrolase (3.1.1.64)
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- C12N 2750/14132: Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
- C12N 2750/14142: virus or viral particle as vehicle, e.g. encapsulating small organic molecule
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- C12N 2750/14171: Demonstrated in vivo effect
- C12N 2830/008: cell type or tissue specific enhancer/promoter combination
- C12N 2830/85: mammalian
- C12N 2840/203: having an IRES
- 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)
- C12Y: ENZYMES

## Abstract

A method for treating an ocular disorder characterized by the defect or absence of a normal gene in the ocular cells of a human or animal subject involves administering to the subject by subretinal injection an effective amount of a recombinant adeno-associated virus carrying a nucleic acid sequence encoding the normal gene under the control of a promoter sequence which expresses the product of the gene in the ocular cells. The ocular cells are preferably retinal pigment epithelial (RPE) cells, and the gene is preferably an RPE-specific gene, e.g., RPE65. The promoter is one that can express the gene product in the RPE cells. Compositions for subretinal administration are useful in this method.

## Claims

### Claim 1

A method for treating a human subject having Leber Congenital Amaurosis, the method comprising: administering to said human subject by subretinal injection a recombinant adeno-associated virus (rAAV) vector comprising a nucleic acid sequence encoding a normal retinal pigment specific epithelial 65 (RPE65) gene operably linked to a chicken beta actin promoter/CMV enhancer, wherein said rAAV vector is administered in a dosage of from 1×109 to 2×1012 rAAV vector in a volume of at least 150 microliters, thereby restoring visual function in said human subject.

### Claim 2 (depends on 1)

The method according to claim 1, wherein said rAAV vector is administered in a volume in the range of 150 microliters to 800 microliters.

### Claim 3 (depends on 2)

The method according to claim 2, wherein said rAAV vector is administered in a volume of about 200 microliters.

### Claim 4 (depends on 2)

The method according to claim 2, wherein said rAAV vector is administered in a volume of about 250 microliters.

### Claim 5 (depends on 2)

The method according to claim 2, wherein said rAAV vector is administered in a volume of about 500 microliters.

### Claim 6 (depends on 2)

The method according to claim 2, wherein said rAAV vector is administered in a volume of about 800 microliters.

### Claim 7 (depends on 2)

The method according to claim 2, wherein said rAAV vector is administered in a dosage in the range of 1×1010 to 2×1011 rAAV vector in a volume in the range of 250 microliters to 500 microliters.

### Claim 8 (depends on 2)

The method according to claim 2, wherein said rAAV vector is administered at a dosage of about 1.5×1011 infectious units.

### Claim 9 (depends on 2)

The method according to claim 2, wherein said ocular cells are retinal pigment epithelial cells.

### Claim 10 (depends on 2)

The method according to claim 2, wherein said rAAV vector is administered in a physiologically acceptable vehicle including one or more of a buffer and a surfactant.

### Claim 11 (depends on 10)

The method according to claim 10, wherein said buffer comprises buffered saline.

### Claim 12

A method for treating a human subject having a mutation in the retinal pigment specific epithelial 65 (RPE65) gene, said method comprising: administering to said human subject by subretinal injection a pharmaceutical composition comprising a physiologically acceptable vehicle and a recombinant adeno-associated virus (rAAV) vector having a nucleic acid sequence encoding a normal RPE65 gene operably linked to a chicken beta actin promoter/CMV enhancer, wherein said rAAV vector is administered at a dosage in the range of 1×109 infectious units to 2×1012 infectious units at a volume of at least 150 microliters, and wherein said mutation in the RPE65 gene results in an ocular disease or disorder in said human subject and wherein administration of said pharmaceutical composition to said human subject results in an improvement to said human subject's visual function.

### Claim 13 (depends on 12)

The method according to claim 12, wherein said pharmaceutical composition is administered at a volume in the range of 150 microliters to 800 microliters.

### Claim 14 (depends on 12)

The method for treating a human subject according to claim 12, wherein said ocular disease or disorder is retinitis pigmentosa or Leber Congenital Amaurosis.

### Claim 15

A method for treating a human subject having an ocular disease or disorder resulting from a mutation in the retinal pigment specific epithelial 65 (RPE65) gene, said method comprising: administering to said human subject by subretinal injection a pharmaceutical composition comprising a physiologically acceptable vehicle and recombinant adeno-associated virus (rAAV) vector having a nucleic acid sequence encoding a normal RPE65 gene operably linked to a chicken beta actin promoter/CMV enhancer, said pharmaceutical composition having a volume of at least 150 microliters and said rAAV vector being present in said pharmaceutical composition in an amount of about 1.5×1011 infectious units; wherein administration of said pharmaceutical composition results in an improvement in said human subject's visual function.

### Claim 16

A method for treating a human subject having Leber Congenital Amaurosis, the method comprising: administering to said human subject by subretinal injection a recombinant adeno-associated virus (rAAV) vector comprising a nucleic acid sequence encoding a normal retinal pigment specific epithelial 65 (RPE65) gene operably linked to a chicken beta actin promoter/CMV enhancer, wherein said rAAV vector is administered in a dosage of from 1×109 to 2×1012 rAAV vector in a volume of at least 150 microliters, thereby improving said human subject's visual function.

### Claim 17 (depends on 16)

The method according to claim 16, wherein said rAAV vector is administered in a volume in the range of 150 microliters to 800 microliters.