Methods for treating chronic kidney disease

Abstract

The present invention relates to methods for treating chronic kidney disease (CKD) including methods for preventing or delaying onset of CKD and methods for preventing exacerbation and progression of CKD. In particular embodiments, the invention provides methods for treating a subject at risk of developing CKD comprising administering to the subject a composition comprising a) a therapeutically effective amount of at least one oligonucleotide compound which inhibits the expression of a human target gene associated with the kidney disease; and b) a pharmaceutically acceptable excipient or carrier, or mixtures thereof, thereby reducing the risk of CKD in the subject.

1 . A method of attentuating acute kidney injury resulting from a renal insult in a subject suffering from chronic kidney disease (CKD) comprising administering to the subject a therapeutically effective dose of an oligonucleotide compound which down-regulates expression of a target gene associated with the acute kidney injury wherein the oligonucleotide compound is administered to the subject in proximity of the renal insult, thereby attenuating acute kidney injury in the CKD subject. 
     
     
         2 . A method of attenuating progression of chronic kidney disease (CKD) in a subject at risk of CKD progression resulting from exposure to recurring renal insults comprising administering to the subject a therapeutically effective dose of an oligonucleotide compound which down-regulates expression of a target gene associated with kidney injury wherein the oligonucleotide compound is administered to the subject in proximity of the renal insult, thereby attenuating progression of chronic kidney disease (CKD) in the subject. 
     
     
         3 . A method of treating or preventing kidney damage in a subject at risk of chronic kidney disease (CKD) associated with exposure to a recurrence of renal insults comprising administering to the subject a therapeutically effective dose of an oligonucleotide compound which down-regulates expression of a target gene associated with kidney damage wherein the oligonucleotide compound is administered to the subject in proximity of each renal insult, thereby treating or preventing kidney damage in the subject. 
     
     
         4 . The method according to any one of  claims 1 - 3  wherein the oligonucleotide compound is administered to the subject within about 72 hrs pre renal insult to 8 hrs post renal insult. 
     
     
         5 . The method according to  claim 4  wherein the oligonucleotide compound is administered to the subject within about 4 hours of the renal insult. 
     
     
         6 . The method according to  claim 4  wherein the oligonucleotide compound is administered to the subject within about 0.5 hours of the renal insult. 
     
     
         7 . The method according to  claim 4  wherein the oligonucleotide is administered to the subject at about 0-4 hours post the renal insult. 
     
     
         8 . The method according to any one of  claims 2 - 3  wherein the renal insult results in acute kidney injury (AKI). 
     
     
         9 . The method according to any one of  claims 1 - 3  wherein the renal insult is associated with one or more of surgery including cardiovascular surgery; exposure to myoglobinuria, ischemia/reperfusion injury; sepsis; urinary tract obstruction; exposure to a nephrotoxin including a nephrotoxic radiocontrast imaging agent, an antibiotic or a chemotherapeutic agent; proteinuria; increased renal ammoniagenesis with interstitial injury; hyperlipidemia; hyperphosphatemia with calcium phosphate deposition. 
     
     
         10 . The method according to  claim 9  wherein renal insult is associated with ischemia/reperfusion injury or exposure to a nephrotoxin or both. 
     
     
         11 . The method according to  claim 9  wherein renal insult is associated with ischemia/reperfusion ensuing during or following cardiovascular surgery or cardiopulmonary surgery. 
     
     
         12 . The method according to  claim 9  wherein the renal insult is associated with myoglobinuria. 
     
     
         13 . The method according to  claim 9  wherein the renal insult is associated with a nephrotoxin. 
     
     
         14 . The method according to claim any one of  claims 1 - 3  wherein the target gene associated with kidney injury is a human gene whose expression is up regulated by the renal insult. 
     
     
         15 . The method according to  claim 14  wherein the target gene is selected from a gene having an mRNA sequence shown in Table 1, set forth in any one of SEQ ID NOS: 1-115. 
     
     
         16 . The method according to  claim 15  wherein the target gene is selected from p53 and CASP2. 
     
     
         17 . The method according to any one of  claims 1 - 3  wherein the oligonucleotide compound is selected from the group consisting of an unmodified siRNA, a chemically modified siRNA, shRNA, an aptamer, an antisense molecule, miRNA, and a ribozyme. 
     
     
         18 . The method according to  claim 17  wherein the oligonucleotide compound is chemically modified siRNA. 
     
     
         19 . The method according to  claim 18  wherein the siRNA has a general double stranded structure:
 5′ (N) x -Z 3′ (antisense strand) 
 3′ Z′-(N′) y -z″ 5′ (sense strand) 
 
       wherein each of N and N′ is a ribonucleotide which may be unmodified or modified, or an unconventional moiety; 
       wherein each of (N)x and (N′)y is an oligonucleotide in which each consecutive N or N′ is joined to the next N or N′ by a covalent bond; 
       wherein Z and Z′ may be present or absent, but if present is independently 1-5 consecutive nucleotides or non-nucleotide moiety covalently attached at the 3′ terminus of the strand in which it is present; 
       wherein z″ may be present or absent, but if present is a capping moiety covalently attached at the 5′ terminus of (N′)y; 
       each of x and y is independently an integer between 18 and 40; 
       wherein the sequence of (N′)y is substantially complementary to the sequence of (N)x; and wherein (N)x comprises an antisense sequence substantially complementary to from about 18 to about 40 consecutive ribonucleotides present in an mRNA of Table 1 set forth in any one of SEQ ID NO:1-115. 
     
     
         20 . The method according to  claim 19  wherein the siRNA is the I5 siRNA compound. 
     
     
         21 . A kit comprising a package containing a therapeutically effective dose of an oligonucleotide compound which down-regulates expression of a gene associated with kidney damage in an amount effective to prevent radiocontrast agent induced kidney damage; and a radiocontrast agent in an amount effective to perform a radiographical examination; and optionally instructions for use. 
     
     
         22 . An oligonucleotide compound which down-regulates expression of a target gene selected from any one of SEQ ID NO:1-115 for use in therapy for preventing or attentuating acute kidney injury resulting from renal insult in a subject suffering from chronic kidney disease (CKD). 
     
     
         23 . An oligonucleotide compound which down-regulates expression of a target gene selected from any one of SEQ ID NO: 1-115 for use in therapy for preventing or attenuating progression of chronic kidney disease (CKD) in a subject at risk of CKD progression resulting from exposure to recurring renal insults. 
     
     
         24 . An oligonucleotide compound which down-regulates expression of a target gene selected from any one of SEQ ID NO:1-115 for use in therapy for treating or preventing kidney damage in a subject at risk of chronic kidney disease (CKD) associated with exposure to a recurrence of renal insults. 
     
     
         25 . Use of oligonucleotide compound which down-regulates expression of a target gene selected from any one of SEQ ID NO: 1-115 for preparation of a medicament for preventing or attentuating acute kidney injury resulting from renal insult in a subject suffering from chronic kidney disease (CKD). 
     
     
         26 . Use of an oligonucleotide compound which down-regulates expression of a target gene selected from any one of SEQ ID NO: 1-115 for preparation of a medicament for preventing or attenuating progression of chronic kidney disease (CKD) in a subject at risk of CKD progression resulting from exposure to recurring renal insults. 
     
     
         27 . Use of an oligonucleotide compound which down regulates expression of a target gene selected from any one of SEQ ID NO: 1-115 for preparation of a medicament for treating or preventing kidney damage in a subject at risk of chronic kidney disease (CKD) associated with exposure to a recurrence of renal insults. 
     
     
         28 . A composition comprising an oligonucleotide compound which down-regulates expression of a target gene selected from any one of SEQ ID NO:1-115 in an amount effective to attenuate chronic kidney disease, and a carrier.