# US 7,745,389 B2 · Methods for treatment of age-related macular degeneration

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- Number: US 7,745,389 B2
- Document ID: US7745389B2
- Status: Granted
- Kind: B2
- Application number: 11/354,559
- Filed: 2006-02-14
- Published: 2007-01-25
- Granted: 2010-06-29
- Earliest claimed: 2005-02-14
- Assignees: University of Iowa Research Foundation
- Inventors: Gregory S. Hageman
- Web page: https://patentgrep.com/patent/US7745389B2

## CPC

- C07K 14/47: from mammals
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 48/00: Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K 48/0058: {Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct}
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 27/02: Ophthalmic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/435: from animals; from humans
- C07K 14/472: {Complement proteins, e.g. anaphylatoxin, C3a, C5a}
- C12N 15/00: Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor (mutants or genetically engineered microorganisms, per se C12N1/00, C12N5/00, C12N7/00; new plants per se A01H; plant reproduction by tissue culture techniques A01H4/00; new animals per se A01K67/00; use of medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases, gene therapy A61K48/00)
- C12N 15/63: Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12Q 1/6883: for diseases caused by alterations of genetic material
- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/00: Drugs for disorders of the senses
- C12Q 2600/136: Screening for pharmacological compounds
- C12Q 2600/156: Polymorphic or mutational markers
- C12Q 2600/158: Expression markers
- C12Q 2600/172: Haplotypes
- 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)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## Abstract

The invention relates to Factor H gene polymorphisms and haplotypes associated with an elevated or a reduced risk of AMD. The invention provides methods and reagents for diagnosis and treatment of AMD.

## Claims

### Claim 1

A method of treating a human patient in need of treatment for age-related macular degeneration (AMD) comprising administering to the patient a composition comprising an inhibitor of the alternative pathway of complement activation, wherein said inhibitor is:
(a) a naturally occurring human Complement Factor H polypeptide comprising residues 19-1231 of SEQ ID NO:5, or a naturally occurring splice variant thereof, or an allelic variant of said human CFH polypeptide or splice variant, with the proviso that residue 62, numbered relative to SEQ ID NO:5, is isoleucine, residue 402 of said human CFH polypeptide, numbered relative to SEQ ID NO:5, is tyrosine, and residue 1210, numbered relative to SEQ ID NO:5, is arginine, wherein the human CFH polypeptide binds complement component 3b (C3b);
(b) a recombinant or purified Complement Factor H polypeptide, wherein the complement factor H polypeptide has at least 90% sequence identity to SEQ ID NO:2 and binds to complement component 3b (C3b), with the proviso that at residue 62, numbered relative to SEQ ID NO:2, the complement factor H polypeptide comprises isoleucine, at residue 402, numbered relative to SEQ ID NO:2, the complement factor H polypeptide comprises tyrosine, and at residue 1210, numbered relative to SEQ ID NO:2, the complement factor H polypeptide comprises arginine; or
(c) a naturally occurring human Complement Factor H polypeptide that binds to complement component 3b (C3b) and has at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:2, with the proviso that residue 62, numbered relative to SEQ ID NO:2, is isoleucine, residue 402, numbered relative to SEQ ID NO:2, is tyrosine, and residue 1210, numbered relative to SEQ ID NO:2, is arginine.

### Claim 2 (depends on 1)

The method of claim 1, wherein the inhibitor is a naturally occurring human Complement Factor H (human CFH) polypeptide comprising residues 19-1231 of SEQ ID NO:5, or a naturally occurring splice variant thereof, or an allelic variant of said human CFH polypeptide or splice variant, with the proviso that residue 62 of said human CFH, numbered relative to SEQ ID NO:5, is isoleucine, residue 402, numbered relative to SEQ ID NO:5, is tyrosine and residue 1210, numbered relative to SEQ ID NO:5, is arginine, wherein the human CFH polypeptide protein binds complement component 3b (C3b).

### Claim 3 (depends on 1)

The method of claim 1, wherein the Factor H polypeptide is administered to the eye.

### Claim 4 (depends on 3)

The method of claim 3, wherein the Factor H polypeptide is administered by intraocular injection.

### Claim 5 (depends on 1)

The method of claim 1, wherein the inhibitor is a recombinant or purified Complement Factor H (CFH) polypeptide and wherein the complement factor H polypeptide has at least 90% sequence identity to SEQ ID NO:2 and binds to complement component 3b (C3b), with the proviso that at residue 62, numbered relative to SEQ ID NO:2, the complement factor H polypeptide comprises isoleucine, at residue 402, numbered relative to SEQ ID NO:2, the complement factor H polypeptide comprises tyrosine, and at residue 1210, numbered relative to SEQ ID NO:2, the complement factor H polypeptide comprises arginine.

### Claim 6 (depends on 5)

The method of claim 5 wherein the complement factor H polypeptide has at least 95% sequence identity to SEQ ID NO:2.

### Claim 7 (depends on 5)

The method of claim 5 wherein the complement factor H polypeptide has a sequence consisting of residues 19-1231 of SEQ ID NO:5.

### Claim 8 (depends on 1)

The method of claim 1, wherein the complement factor H polypeptide is a recombinant polypeptide.

### Claim 9 (depends on 1)

The method of claim 1, wherein the complement factor H polypeptide is purified from blood.

### Claim 10 (depends on 1)

The method of claim 1, wherein the complement factor H polypeptide is administered systemically.

### Claim 11 (depends on 1)

The method of claim 1, wherein the composition comprises a pharmaceutically acceptable carrier.

### Claim 12 (depends on 1)

The method of claim 1, wherein the composition is a sterile pathogen-free preparation.

### Claim 13

A method of treating a patient diagnosed with or at risk for developing age-related macular degeneration (AMD) comprising administering a composition comprising a recombinant or purified complement factor H polypeptide to the patient, wherein
(a) the complement factor H polypeptide has at least 90% sequence identity to SEQ ID NO:2, comprises isoleucine at residue 62 numbered relative to SEQ ID NO:2, comprises tyrosine at residue 402 numbered relative to SEQ ID NO:2, and binds complement component 3b (C3b), or
(b) is a biologically active fragment of (a) that comprises isoleucine at residue 62 numbered relative to SEQ ID NO:2 and binds C3b.

### Claim 14 (depends on 1, 13)

The method of claim 1 or claim 13 wherein the patient has been diagnosed with early stage AMD.

### Claim 15 (depends on 14)

The method of claim 14 wherein the patient shows signs of drusen development.

### Claim 16 (depends on 1, 13)

The method of claim 1 or claim 13 wherein the patient has signs or symptoms of AMD.

### Claim 17 (depends on 1, 13)

The method of claim 1 or claim 13 wherein the patient has been diagnosed as having a propensity to develop AMD.

### Claim 18 (depends on 1)

The method of claim 1, wherein said inhibitor is a naturally occurring human Complement Factor H (human CFH) polypeptide that binds to complement component 3b (C3b) and has at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:2, with the proviso that residue 62, numbered relative to SEQ ID NO:2, is isoleucine, residue 402, numbered relative to SEQ ID NO:2, is tyrosine, and residue 1210, numbered relative to SEQ ID NO:2, is arginine.

### Claim 19 (depends on 18)

The method of claim 18 wherein the complement factor H polypeptide has at least 95% sequence identity to SEQ ID NO:2.

### Claim 20 (depends on 2)

The method of claim 2 wherein the patient's genome comprises a CFH allele encoding a CFH polypeptide having histidine at position 402.

### Claim 21 (depends on 5)

The method of claim 5 wherein the patient's genome comprises a CFH allele encoding a CFH protein having histidine at position 402.

### Claim 22 (depends on 18)

The method of claim 18 wherein the patient's genome comprises a CFH allele encoding a CFH protein having histidine at position 402.