# US 8,569,258 B2 · Low density lipoprotein receptor-mediated siRNA delivery

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- Number: US 8,569,258 B2
- Document ID: US8569258B2
- Status: Granted
- Kind: B2
- Application number: 13/584,256
- Filed: 2012-08-13
- Published: 2012-12-13
- Granted: 2013-10-29
- Earliest claimed: 2007-11-15
- Assignees: Alcon Research, Ltd.
- Applicants: Jon E. Chatterton
- Inventors: Jon E. Chatterton
- Web page: https://patentgrep.com/patent/US8569258B2

## CPC

- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 38/16: Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof {(enzyme inhibitors A61K38/005)}
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 47/6425: {the peptide or protein in the drug conjugate being a receptor, e.g. CD4, a cell surface antigen, i.e. not a peptide ligand targeting the antigen, or a cell surface determinant, i.e. a part of the surface of a cell}
- A61K 47/6455: {Polycationic oligopeptides, polypeptides or polyamino acids, e.g. for complexing nucleic acids}
- A61K 47/6807: {the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/12: Antihypertensives
- A61P 27/02: Ophthalmic agents
- A61P 27/04: Artificial tears; Irrigation solutions
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12N 15/1138: {against receptors or cell surface proteins}
- C07K 2319/74: containing a fusion for binding to a cell surface receptor
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/351: Conjugate
- C12N 2310/3513: Protein; Peptide
- C12N 2310/3515: Lipophilic moiety, e.g. cholesterol
- C12N 2320/30: Special therapeutic applications
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- C12N 2320/35: based on a specific dosage / administration regimen
- 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)
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The invention provides interfering RNA molecule-ligand conjugates useful as a delivery system for delivering interfering RNA molecules to a cell in vitro or in vivo. The conjugates comprise a ligand that can bind to a low density lipoprotein receptor (LDLR) or LDLR family member. Therapeutic uses for the conjugates are also provided.

## Claims

### Claim 1

A method of delivering an interfering RNA molecule to an eye of a patient, comprising administering to an eye of the patient an interfering RNA delivery conjugate comprising an interfering RNA molecule, a ligand that comprises the LDLR biding domain of apolipoprotein E (apoE), and an HA2 peptide.

### Claim 2 (depends on 1)

The method of claim 1, wherein the ligand comprises the LDLR binding domain of apolipoprotein B (apoB).

### Claim 3 (depends on 1)

The method of claim 1, wherein the ligand comprises an LDLR-specific antibody or a fragment thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the interfering RNA molecule is linked to the ligand via a nucleic acid binding protein.

### Claim 5 (depends on 1)

The method of claim 1, wherein the interfering RNA molecule is linked to the ligand via a polycation.

### Claim 6 (depends on 5)

The method of claim 5, wherein the polycation is polylysine.

### Claim 7 (depends on 1)

The method of claim 1, wherein the interfering RNA molecule is linked to the ligand via a 7×Arg peptide, 8×Arg peptide, 9×Arg peptide, 10×Arg peptide, or 11×Arg peptide.

### Claim 8 (depends on 7)

The method of claim 7, wherein the interfering RNA molecule is linked to the ligand via a 9×Arg peptide.

### Claim 9 (depends on 1)

The method of claim 1, wherein the interfering RNA molecule is a siRNA, miRNA, or shRNA.

### Claim 10 (depends on 1)

The method of claim 1, wherein the interfering RNA molecule is covalently linked to the ligand.

### Claim 11 (depends on 1)

The method of claim 1, wherein the interfering RNA delivery conjugate is administered by intraocular injection, subconjunctival injection, intravitreal injection, or anterior or posterior juxtascleral injection.

### Claim 12 (depends on 1)

The method of claim 1, wherein the patient has ocular angiogenesis, dry eye, an ocular inflammatory condition, ocular hypertension, or glaucoma.