# US 9,040,494 B2 · RNAi-mediated inhibition of frizzled related protein-1 for treatment of glaucoma

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- Number: US 9,040,494 B2
- Document ID: US9040494B2
- Status: Granted
- Kind: B2
- Application number: 13/429,913
- Filed: 2012-03-26
- Published: 2012-07-12
- Granted: 2015-05-26
- Earliest claimed: 2005-03-11
- Assignees: Novartis AG
- Applicants: Abbot F. Clark; Wan-Heng Wang; Loretta Graves McNatt; Jon E. Chatterton
- Inventors: Abbot F. Clark; Wan-Heng Wang; Loretta Graves McNatt; Jon E. Chatterton
- Web page: https://patentgrep.com/patent/US9040494B2

## CPC

- 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)}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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 2310/111: spanning the whole gene, or a large part of it
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/316: Phosphonothioates
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/351: Conjugate
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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

## Abstract

RNA interference is provided for inhibition of Frizzled Related Protein-1 mRNA expression, in particular, for treating patients having glaucoma or at risk of developing glaucoma.

## Claims

### Claim 1

A method of attenuating expression of Frizzled Related Protein-1 mRNA of a subject, comprising:
administering to an eye of the subject a composition comprising an effective amount of interfering RNA and a pharmaceutically acceptable carrier, the interfering RNA comprising:
a sense nucleotide strand, an antisense nucleotide strand, and a region of at least near-perfect contiguous complementarity between the sense and antisense strands of at least 19 nucleotides;
wherein the sense strand is 19 to 21 nucleotides, and the antisense strand is 19 to 21 nucleotides and hybridizes to a nucleic acid sequence of SEQ ID NO: 98, wherein the thymines are replaced with uracils,
wherein the expression of Frizzled Related Protein-1 mRNA is attenuated thereby.

### Claim 2 (depends on 1)

The method of claim 1 wherein the subject is a human and the human has glaucoma.

### Claim 3 (depends on 1)

The method of claim 1 wherein the subject is a human and the human is at risk of developing glaucoma.

### Claim 4 (depends on 1)

The method of claim 1 wherein the antisense strand of the interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:1 comprising nucleotide 3080.

### Claim 5 (depends on 1)

The method of claim 1 further comprising administering to the subject a second interfering RNA having a length of 19 to 49 nucleotides and comprising:
a sense nucleotide strand, an antisense nucleotide strand, and a region of at least near-perfect complementarity of at least 19 nucleotides;
wherein the antisense strand of the second interfering RNA hybridizes under physiological conditions to a second portion of mRNA corresponding to SEQ ID NO:1 or SEQ ID NO:191, and the antisense strand has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the second hybridizing portion of mRNA corresponding to SEQ ID NO:1 or SEQ ID NO:191, respectively.

### Claim 6 (depends on 1)

The method of claim 1 wherein the sense nucleotide strand and the antisense nucleotide strand are connected by a loop nucleotide strand.

### Claim 7 (depends on 1)

The method of claim 1 wherein the composition is administered via a topical, intravitreal, transcleral, periocular, conjunctival, subtenon, intracameral, subretinal, subconjunctival, retrobulbar, intracanalicular, or suprachoroidal route.

### Claim 8 (depends on 1)

The method of claim 1 wherein the interfering RNA is administered via in vivo expression from an expression vector capable of expressing the interfering RNA.

### Claim 9

A method of treating glaucoma in a subject in need thereof, comprising:
administering to an eye of the subject a composition comprising an effective amount of interfering RNA, and a pharmaceutically acceptable carrier, the interfering RNA comprising a sense nucleotide strand, an antisense nucleotide strand, and a region of at least near-perfect contiguous complementarity between the sense and antisense strands of at least 19 nucleotides;
wherein the sense strand is 19 to 21 nucleotides, and the antisense strand is 19 to 21 nucleotides and hybridizes to a nucleic acid sequence of NO: 98, wherein the thymines are replaced with uracils,
wherein the glaucoma is treated thereby.

### Claim 10 (depends on 9)

The method of claim 9 wherein the subject is a human and the human has glaucoma.

### Claim 11 (depends on 9)

The method of claim 9 wherein the antisense strand of the interfering RNA is designed to target an mRNA corresponding to SEQ ID NO:1 comprising nucleotide 3080.

### Claim 12 (depends on 9)

The method of claim 9 further comprising administering to the subject a second interfering RNA having a length of 19 to 49 nucleotides and comprising:
a sense nucleotide strand, an antisense nucleotide strand, and a region of at least near-perfect complementarity of at least 19 nucleotides;
wherein the antisense strand of the second interfering RNA hybridizes under physiological conditions to a second portion of mRNA corresponding to SEQ ID NO:1 or SEQ ID NO:191, and the antisense strand has a region of at least near-perfect contiguous complementarity of at least 19 nucleotides with the second hybridizing portion of mRNA corresponding to SEQ ID NO:1 or SEQ ID NO:191, respectively.

### Claim 13 (depends on 9)

The method of claim 9 wherein the sense nucleotide strand and the antisense nucleotide strand are connected by a loop nucleotide strand.

### Claim 14 (depends on 9)

The method of claim 9 wherein the composition is administered via a topical, intravitreal, transcleral, periocular, conjunctival, subtenon, intracameral, subretinal, subconjunctival, retrobulbar, intracanalicular or suprachoroidal route.

### Claim 15 (depends on 9)

The method of claim 9 wherein the interfering RNA is administered via in vivo expression from an expression vector capable of expressing the interfering RNA.

### Claim 16 (depends on 9)

The method of claim 9 wherein the composition is administered via ocular injection.