# US 8,785,408 B2 · Compositions and methods for reducing or protecting against delayed graft function (DGF)

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- Number: US 8,785,408 B2
- Document ID: US8785408B2
- Status: Granted
- Kind: B2
- Application number: 12/452,321
- Filed: 2008-06-26
- Published: 2010-09-02
- Granted: 2014-07-22
- Earliest claimed: 2007-06-27
- Assignees: Quark Pharmaceuticals, Inc.
- Applicants: Elena Feinstein; Shai Erlich
- Inventors: Elena Feinstein; Shai Erlich
- Web page: https://patentgrep.com/patent/US8785408B2

## 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)}
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2320/11: for the determination of target sites, i.e. of active nucleic acids
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to one or more inhibitors, in particular siRNA compounds, which down-regulate the expression of a pro-apoptotic gene selected from the group consisting of TP53; HTRA2; KEAP1; SHC1-SHC, ZNHIT1, LGALS3 and HI95. The invention also relates to a pharmaceutical composition comprising the compound, and a pharmaceutically acceptable carrier. The present invention further provides methods of treating a subject afflicted with a disease or a condition associated with those genes, comprising administering to the subject a pharmaceutical composition in a therapeutically effective dose so as to thereby treat the subject.

## Claims

### Claim 1

A method of reducing Delayed Graft Function (DGF) in a recipient of a kidney transplant from a deceased donor, comprising only between 15 minutes and 4 hours following revascularization of the transplanted kidney, intravenously administering to the recipient, a composition which comprises a double-stranded RNA compound having the structure:
5′ (N)x-Z 3′ (antisense strand)
3′ Z′-(N′)y 5′ (sense strand)
wherein each N and N′ is a ribonucleotide which may be unmodified or modified in its sugar residue;
wherein each of (N)x and (N′)y is an oligonucleotide in which each consecutive ribonucleotide is joined to the next ribonucleotide by a covalent bond and each of x and y is an integer between 18 and 40;
wherein in each of (N)x and (N′)y the ribonucleotides alternate between modified ribonucleotides and unmodified ribonucleotides, each modified ribonucleotide being a 2′-O-methyl sugar modified ribonucleotide;
wherein each of Z and Z′ may be present or absent, but if present is 1-5 deoxyribonucleotides covalently attached at the 3′ terminus of the oligonucleotide in which it is present;
wherein the sequence of the antisense strand comprises the sequence 5′ UGAAGGGUGAAAUAUUCUC 3′ (SEQ ID NO:2) and the sequence of the sense strand comprises the sequence 5′ GAGAAUAUUUCACCCUUCA 3′ (SEQ ID NO:1); and
wherein the composition comprises an amount of the compound effective to down-regulate expression of a p53 gene, and thereby reduce Delayed Graft Function (DGF) in the recipient.

### Claim 2 (depends on 1)

The method of claim 1, wherein the composition is administered as a single, slow intravenous push.

### Claim 3 (depends on 1)

The method of claim 1, wherein x=y=19.

### Claim 4 (depends on 2)

The method of claim 2, wherein the ribonucleotide at the 5′ terminus and the ribonucleotide at the 3′ terminus of the antisense strand are 2′-O-methyl modified in their sugar residues, and the ribonucleotide at the 5′ terminus and the ribonucleotide at the 3′ terminus of the sense strand are unmodified in their sugar residues; and wherein both of Z and Z′ are absent.

### Claim 5 (depends on 1)

The method of claim 1, wherein the antisense strand and the sense strand may be phosphorylated or non-phosphorylated at their 3′ terminus or their 5′ terminus or both.

### Claim 6 (depends on 1)

The method of claim 1, wherein the DGF is cold ischemia-associated DGF.

### Claim 7 (depends on 1)

The method of claim 1, wherein the amount of the double-stranded RNA compound is between 0.1 and 50 mg/kg body weight of the recipient.

### Claim 8 (depends on 7)

The method of claim 7, wherein the amount of the double-stranded RNA compound is between 0.5 and 10 mg/kg body weight of the recipient.

### Claim 9

A method of protecting a recipient of a kidney transplant from a deceased donor from Delayed Graft Function (DGF) comprising only between 15 minutes and 4 hours following revascularization of the transplanted kidney intravenously administering to the recipient a composition which comprises a double-stranded RNA compound having the structure:
5′ UGAAGGGUGAAAUAUUCUC 3′ (antisense strand;
SEQ ID NO: 2)
3′ ACUUCCCACUUUAUAAGAG 5′ (sense strand;
SEQ ID NO: 1)
wherein each of A, C, U and G is an unmodified ribonucleotide or a 2′-O-methyl sugar modified ribonucleotide and each consecutive ribonucleotide is joined to the next ribonucleotide by a covalent bond;
wherein in the antisense strand the first, third, fifth, seventh, ninth, eleventh, thirteenth, fifteenth, seventeenth and nineteenth ribonucleotide are 2′-O-methyl sugar modified ribonucleotides;
wherein in the sense strand the second, fourth, sixth, eighth, tenth, twelfth, fourteenth, sixteenth and eighteenth ribonucleotide are 2′-O-methyl sugar modified ribonucleotides; and
wherein the composition comprises an amount of the compound effective to down-regulate expression of a p53 gene, and thereby protect the recipient from Delayed Graft Function (DGF).

### Claim 10 (depends on 9)

The method of claim 9, wherein the DGF is cold ischemia-associated DGF.

### Claim 11 (depends on 9)

The method of claim 9, wherein the donor died from brain or cardiac death.

### Claim 12 (depends on 9)

The method of claim 9, wherein the amount of the double-stranded RNA compound is between 0.1 and 50 mg/kg body weight of the recipient.

### Claim 13 (depends on 12)

The method of claim 12, wherein the amount of the double-stranded RNA compound is between 0.5 and 10 mg/kg body weight of the recipient.

### Claim 14 (depends on 1)

The method of claim 1, wherein the donor died from brain or cardiac death.

### Claim 15 (depends on 1)

The method of claim 1, wherein the composition is administered as a single administration.

### Claim 16 (depends on 9)

The method of claim 9, wherein both the antisense strand and the sense strand are non-phosphorylated at the 3′ termini and the 5′ termini.

### Claim 17 (depends on 9)

The method of claim 9, wherein the composition is administered as a single administration.

### Claim 18 (depends on 17)

The method of claim 17, wherein the composition is administered as a single, slow intravenous push.

### Claim 19 (depends on 1)

The method of claim 1, wherein the amount of the double-stranded RNA compound is 10 mg/kg body weight of the recipient.

### Claim 20 (depends on 9)

The method of claim 9, wherein the amount of the double-stranded RNA compound is 10 mg/kg body weight of the recipient.