Methods for Treatment of 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.