Methods for treatment of polycystic kidney disease

Abstract

Provided herein are methods for the treatment of polycystic kidney disease, including autosomal dominant polycystic kidney disease, using modified oligonucleotides targeted to miR-17.

1 . A method of treating polycystic kidney disease comprising administering to a subject in need thereof a compound comprising a modified oligonucleotide consisting of 8 to 25 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is complementary to miR-17. 
     
     
         2 . The method of  claim 1 , wherein the subject has polycystic kidney disease. 
     
     
         3 . The method of  claim 1 , wherein the subject is suspected of having polycystic kidney disease. 
     
     
         4 . The method of  claim 1  wherein the subject has been diagnosed as having polycystic kidney disease prior to administering the modified oligonucleotide. 
     
     
         5 . The method of  claim 1  wherein the subject, prior to administration of the modified oligonucleotide, was determined to have an increased level of miR-17 in the kidney, urine or blood of the subject. 
     
     
         6 . The method of  claim 1 , wherein the polycystic kidney disease is autosomal recessive polycystic kidney disease or autosomal dominant polycystic kidney disease. 
     
     
         7 . The method of  claim 1 , wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease. 
     
     
         8 . The method of  claim 1 , wherein the subject has a mutation selected from a mutation in the PKD1 gene or a mutation in the PKD2 gene. 
     
     
         9 . The method of  claim 1 , wherein the subject has increased total kidney volume. 
     
     
         10 . The method of  claim 1 , wherein the subject has hypertension. 
     
     
         11 . The method of  claim 1 , wherein the subject has impaired kidney function. 
     
     
         12 . The method of  claim 1 , wherein the subject is in need of improved kidney function. 
     
     
         13 . The method of  claim 1 , wherein the administering:
 a) improves kidney function in the subject;   b) delays the worsening of kidney function in the subject;   c) reduces total kidney volume in the subject;   d) slows the increase in total kidney volume in the subject;   e) inhibits cyst growth in the subject;   f) slows the increase in cyst growth in the subject;   g) reduces kidney pain in the subject;   h) slows the increase in kidney pain in the subject;   i) delays the onset of kidney pain in the subject;   j) reduces hypertension in the subject;   k) slows the worsening of hypertension in the subject;   l) delays the onset of hypertension in the subject;   m) reduces fibrosis in the kidney of the subject;   n) slows the worsening of fibrosis in the kidney of the subject;   o) delays the onset of end stage renal disease in the subject;   p) delays time to dialysis for the subject;   q) delays time to renal transplant for the subject; and/or   r) improves life expectancy of the subject.   
     
     
         14 . The method of  claim 1 , wherein the administering:
 s) reduces albuminuria in the subject;   t) slows the worsening of albuminuria in the subject;   u) delays the onset of albuminuria in the subject;   v) reduces hematuria in the subject;   w) slows the worsening of hematuria in the subject;   x) delays the onset of hematuria in the subject;   y) reduces blood urea nitrogen in the subject;   z) reduces creatinine in the blood of the subject;   aa) improves creatinine clearance in the subject;   bb) reduces albumin:creatinine ratio in the subject;   cc) improves glomerular filtration rate in the subject;   dd) slows the worsening of glomerular filtration rate in the subject;   ee) reduces neutrophil gelatinase-associated lipocalin (NGAL) protein in the urine of the subject; and/or   ff) reduces kidney injury molecule-1 (KIM-1) protein in the urine of the subject.   
     
     
         15 . The method of  claim 1 , comprising:
 gg) measuring total kidney volume in the subject;   hh) measuring hypertension in the subject;   ii) measuring kidney pain in the subject;   jj) measuring fibrosis in the kidney of the subject;   kk) measuring blood urea nitrogen in the blood of the subject;   ll) measuring creatinine in the blood of the subject;   mm) measuring creatinine clearance in the subject;   nn) measuring albuminuria in the subject;   oo) measuring albumin:creatinine ratio in the subject;   pp) measuring glomerular filtration rate in the subject;   qq) measuring neutrophil gelatinase-associated lipocalin (NGAL) protein in the urine of the subject; and/or   rr) measuring kidney injury molecule-1 (KIM-1) protein in the urine of the subject.   
     
     
         16 . The method of  claim 9 , wherein the total kidney volume is height-adjusted kidney volume. 
     
     
         17 . The method of  claim 13 , wherein the cyst is present in one or more kidneys in the subject. 
     
     
         18 . The method of  claim 13 , wherein the cyst is present in the liver of the subject. 
     
     
         19 . The method of  claim 1 , comprising administering at least one additional therapy that is an anti-hypertensive agent. 
     
     
         20 . The method of  claim 1 , comprising administering at least one additional therapy selected from an angiotensin II converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), a diuretic, a calcium channel blocker, a kinase inhibitor, an adrenergic receptor antagonist, a vasodilator, a benzodiazepine, a renin inhibitor, an aldosterone receptor antagonist, an endothelin receptor blocker, an mammalian target of rapamycin (mTOR) inhibitor, a hormone analogue, a vasopressin receptor 2 antagonist, an aldosterone receptor antagonist, dialysis, and kidney transplant. 
     
     
         21 . The method of  claim 20  wherein the angiotensin II converting enzyme (ACE) inhibitor is selected from captopril, enalapril, lisinopril, benazepril, quinapril, fosinopril, and ramipril. 
     
     
         22 . The method of  claim 20  wherein the angiotensin II receptor blocker (ARB) is selected from candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, and eprosartan. 
     
     
         23 . The method of  claim 20  wherein the vasopressin receptor 2 antagonist is tolvaptan. 
     
     
         24 . The method of  claim 20 , wherein the aldosterone receptor antagonist is spironolactone. 
     
     
         25 . The method of  claim 20 , wherein the kinase inhibitor is selected from bosutinib and KD019. 
     
     
         26 . The method of  claim 20 , wherein the mTOR inhibitor is selected from everolimus, rapamycin, and sirolimus. 
     
     
         27 . The method of  claim 20 , the hormone analogue is selected from somatostatin and adrenocorticotrophic hormone. 
     
     
         28 . The method of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary, is at least 95% complementary, or is 100% complementary to the nucleobase sequence of miR-17 (SEQ ID NO: 1). 
     
     
         29 . The method of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide comprises the nucleobase sequence 5′-GCACTTTG-3′ (SEQ ID NO: 3), wherein each T in the nucleobase sequence is independently selected from a T and a U. 
     
     
         30 . The method of  claim 1 , wherein the modified oligonucleotide consists of 8 to 12 linked nucleosides. 
     
     
         31 . The method of  claim 1 , wherein the modified oligonucleotide consists of 12 to 25 linked nucleosides. 
     
     
         32 . The method of  claim 1 , wherein the modified oligonucleotide consists of 15 to 25 linked nucleosides. 
     
     
         33 . The method of  claim 1 , wherein the modified oligonucleotide consists of 17 to 23 linked nucleosides. 
     
     
         34 . The method of  claim 1 , wherein the modified oligonucleotide consists of 8, 9, 10, 11 or 12 linked nucleosides. 
     
     
         35 . The method of  claim 1 , wherein the modified oligonucleotide consists of 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 linked nucleosides. 
     
     
         36 . The method of  claim 1 , wherein the modified oligonucleotide consists of 15, 16, 17, 18, 19, 20, 21, or 22 linked nucleosides. 
     
     
         37 . The method of  claim 1 , wherein the modified oligonucleotide consists of 17, 18, 19, 20, 21, 22, or 23 linked nucleosides. 
     
     
         38 . The method of  claim 1 , wherein the modified oligonucleotide comprises at least one modified nucleoside. 
     
     
         39 . The method of  claim 38 , wherein the modified nucleoside is selected from an S-cEt nucleoside, a 2′-O-methoxyethyl nucleoside, and an LNA nucleoside. 
     
     
         40 . The method of  claim 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage. 
     
     
         41 . The method of  claim 1 , wherein each internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage. 
     
     
         42 . The method of  claim 40 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         43 . The method of  claim 1 , wherein the compound consists of the modified oligonucleotide. 
     
     
         44 . The method of  claim 1 , comprising administering a therapeutically effective amount of the compound. 
     
     
         45 . (canceled)