Methods for Treatment of Alport Syndrome

Abstract

Provided herein are methods for the treatment of Alport Syndrome, using modified oligonucleotides targeted to miR-21. In certain embodiments, a modified oligonucleotide targeted to miR-21 improves kidney function and/or reduces fibrosis in subjects having Alport Syndrome. In certain embodiments, administration of a modified oligonucleotide targeted to miR-21 delays the onset of end-stage renal disease in a subject having Alport Syndrome. In certain embodiments, a modified oligonucleotide targeted to miR-21 delays the need for dialysis or kidney transplant in a subject having Alport Syndrome.

1 .- 30 . (canceled) 
     
     
         31 . A method of treating Alport Syndrome comprising administering to a subject having or suspected of having Alport Syndrome: (i) a pharmaceutical composition comprising a therapeutically effective amount of a modified oligonucleotide consisting of 19 linked nucleosides and having the structure 5′-A E C S ATC S AGTC S TGAU S AAGC S TA E -3′ (SEQ ID NO: 3), where nucleosides not followed by a subscript are β-D-deoxyribonucleosides;
 nucleosides followed by a subscript “E” are 2′-MOE nucleosides; nucleosides followed by a subscript “S” are S-cEt nucleosides, and each internucleoside linkage is a phosphorothioate internucleoside linkage; and (ii)_at least one additional therapy selected from an angiotensin II converting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), an anti-hypertensive agent, a vitamin D analog, an oral phosphate binder, dialysis, and kidney transplant. 
 
     
     
         32 . The method of  claim 31 , wherein the subject has been diagnosed as having Alport Syndrome prior to administering the modified oligonucleotide and the at least one additional therapy. 
     
     
         33 . The method of  claim 31 , wherein the subject, prior to administration of the modified oligonucleotide and the at least one additional therapy, was determined to have an increased level of miR-21 in the kidney, urine or blood of the subject. 
     
     
         34 . The method of  claim 31 , wherein the administering:
 a) improves kidney function;   b) delays the onset of end stage renal disease;   c) delays time to dialysis;   d) delays time to renal transplant; and/or   e) improves life expectancy.   
     
     
         35 . The method of  claim 31 , wherein the administering:
 a) reduces hematuria;   b) delays the onset of hematuria;   c) reduces proteinuria;   d) delays the onset of proteinuria;   e) reduces kidney fibrosis;   f) slows further progression of fibrosis; and/or   g) halts further progression of fibrosis.   
     
     
         36 . The method of  claim 31 , wherein the subject has a mutation selected from a mutation in the gene encoding the alpha 3 chain of type IV collagen, a mutation in the gene encoding the alpha 4 chain of type IV collagen, or a mutation in the gene encoding the alpha 5 chain of type IV collagen. 
     
     
         37 . The method of  claim 31 , wherein the subject is male. 
     
     
         38 . The method of  claim 31 , wherein the subject is female. 
     
     
         39 . The method of  claim 31 , wherein the subject is identified as having hematuria, and/or proteinuria. 
     
     
         40 . The method of  claim 31 , wherein the subject has reduced kidney function. 
     
     
         41 . The method of  claim 31 , wherein the subject is in need of improved kidney function. 
     
     
         42 . The method of  claim 31  comprising:
 a) measuring blood urea nitrogen in the blood of the subject; 
 b) measuring creatinine in the blood of the subject; 
 c) measuring creatinine clearance in the subject; 
 d) measuring proteinuria in the subject; 
 e) measuring albumin:creatinine ratio in the subject; 
 f) measuring glomerular filtration rate in the subject; 
 g) measuring cystatin C in the subject; 
 h) measuring β-trace protein (BTP) in the blood of the subject; 
 i) measuring 2-microglobulin in the blood of the subject; 
 j) measuring N-acetyl-β-D-glucosaminidase (NAG) protein in the urine of the subject; 
 k) measuring neutrophil gelatinase-associated lipocalin (NGAL) protein in the urine of the subject; 
 l) measuring kidney injury molecule-1 (KIM-1) protein in the urine of the subject; 
 m) measuring interleukin-18 (IL-18) protein in the urine of the subject; 
 n) measuring monocyte chemoattractant protein (MCP1) levels in the urine of the subject; 
 o) measuring connective tissue growth factor (CTGF) levels in the urine of the subject; 
 p) measuring collagen IV fragments in the urine of the subject; 
 q) measuring collagen III fragments in the urine of the subject; and/or 
 r) measuring podocyte protein levels in the urine of the subject, wherein the podocyte protein is selected from nephrin and podocin. 
 
     
     
         43 . The method of  claim 31 , wherein the administering improves one or more markers of kidney function in the subject, selected from:
 a) reduced blood urea nitrogen in the subject;   b) reduced creatinine in the blood of the subject;   c) improved creatinine clearance in the subject;   d) reduced proteinuria in the subject;   e) reduced albumin:creatinine ratio in the subject;   f) improved glomerular filtration rate in the subject;   g) reduced cystatin C in the blood of the subject;   h) reduced β-trace protein (BTP) in the blood of the subject;   i) reduced 2-microglobulin (B2M) in the blood of a subject;   j) reduced NAG protein in the urine of the subject;   k) reduced NGAL protein in the urine of the subject;   l) reduced KIM-1 protein in the urine of the subject;   m) reduced IL-18 protein in the urine of the subject;   n) reduced monocyte chemoattractant protein (MCP1) levels in the urine of the subject;   o) reduced connective tissue growth factor (CTGF) levels in the urine of the subject;   p) reduced collagen IV fragments in the urine of the subject;   q) reduced collagen III fragments in the urine of the subject; and/or   r) reduced podocyte protein levels in the urine of the subject, wherein the podocyte protein is selected from nephrin and podocin.   
     
     
         44 . The method of  claim 35 , wherein the proteinuria is albuminuria. 
     
     
         45 . The method of  claim 44 , wherein the albuminuria is high normal albuminuria, microalbuminuria, or macroalbuminuria. 
     
     
         46 . The method of  claim 31 , wherein the Alport Syndrome is the X-linked form of Alport Syndrome. 
     
     
         47 . The method of  claim 31 , wherein the Alport Syndrome is the autosomal form of Alport Syndrome. 
     
     
         48 . The method of  claim 31 , wherein the angiotensin II converting enzyme (ACE) inhibitors is selected from captopril, enalapril, lisinopril, benazepril, quinapril, fosinopril, and ramipril. 
     
     
         49 . The method of  claim 31 , wherein the angiotensin II receptor blockers (ARB) is selected from candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, and eprosartan.