Methods for treatment of alport syndrome

1. A method of treating Alport Syndrome comprising administering to a subject having or suspected of having Alport Syndrome a modified oligonucleotide consisting of 12 to 25 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is complementary to miR-21.

2. The method of claim 1 wherein the subject has been diagnosed as having Alport Syndrome prior to administering the modified oligonucleotide.

3. The method of claim 1 wherein the subject, prior to administration of the modified oligonucleotide, was determined to have an increased level of miR-21in the kidney, urine or blood of the subject.

4. The method of claim 1 , 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.

5. The method of claim 1 , 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.

6. The method of claim 1 , 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.

7. The method of claim 1 , wherein the subject is identified as having hematuria, and/or proteinuria.

8. The method of claim 1 , wherein the subject has reduced kidney function.

9. The method of claim 1 , wherein the subject is in need of improved kidney function.

10. The method of claim 1 , 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.

11. The method of claim 1 , 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.

12. The method of claim 5 , wherein the proteinuria is albuminuria.

13. The method of claim 12 , wherein the albuminuria is high normal albuminuria, microalbuminuria, or macroalbuminuria.

14. The method of claim 1 , wherein the Alport Syndrome is the X-linked form of Alport Syndrome.

15. The method of claim 1 , wherein the Alport Syndrome is the autosomal form of Alport Syndrome.

16. 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), an anti-hypertensive agent, a vitamin D analog, an oral phosphate binder, dialysis, and kidney transplant.

17. The method of claim 16 , wherein the angiotensin II converting enzyme (ACE) inhibitor is selected from captopril, enalapril, lisinopril, benazepril, quinapril, fosinopril, and ramipril; and wherein the angiotensin II receptor blocker (ARB) is selected from candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, and eprosartan.

18. The method of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to the nucleobase sequence of miR-21(SEQ ID NO: 1).

19. The method of claim 1 , wherein the modified oligonucleotide consists of 15 to 25 linked nucleosides.

20. The method of claim 1 , wherein the modified oligonucleotide consists of 15, 16, 17, 18, 19, 20, 21, or 22 linked nucleosides.

21. The method of claim 1 , wherein the modified oligonucleotide comprises at least one modified nucleoside.

22. The method of claim 21 , wherein the modified nucleoside is selected from an S-cEt nucleoside, a 2′-O-methoxyethyl nucleoside, and an LNA nucleoside.

23. The method of claim 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.

24. The method of claim 1 , wherein each internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.

25. The method of claim 24 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

26. The method of claim 1 , wherein the modified oligonucleotide has the structure 5′-A E C S ATC S AGTC S TGAU S AAGC S TA E -3′, where nucleosides not followed by a subscript indicate β-D-deoxyribonucleosides; nucleosides followed by a subscript “E” indicate 2′-MOE nucleosides; nucleosides followed by a subscript “S” indicate S-cEt nucleosides, and each internucleoside linkage is a phosphorothioate internucleoside linkage.