Methods for Treatment of Alport Syndrome
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 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.
34 . 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.
35 . The method of claim 31 , wherein the subject has a mutation in the gene encoding the alpha 3 chain of type IV collagen, the alpha 4 chain of type IV collagen, or the alpha 5 chain of type IV collagen.
36 . The method of claim 31 , wherein the subject is identified as having hematuria, and/or proteinuria.
37 . The method of claim 31 , wherein the subject has reduced kidney function.
38 . 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.
39 . The method of claim 34 , wherein the proteinuria is albuminuria.
40 . The method of claim 39 , wherein the albuminuria is high normal albuminuria, microalbuminuria, or macroalbuminuria.
41 . The method of claim 31 , wherein the Alport Syndrome is the X-linked form of Alport Syndrome.
42 . The method of claim 31 , wherein the Alport Syndrome is the autosomal form of Alport Syndrome.
43 . The method of claim 31 , wherein the method comprises administering an angiotensin II converting enzyme (ACE) inhibitor selected from captopril, enalapril, lisinopril, benazepril, quinapril, fosinopril, and ramipril.
44 . The method of claim 31 , wherein the method comprises administering an angiotensin II receptor blocker (ARB) selected from candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, and eprosartan.
45 . The method of claim 31 , wherein the modified oligonucleotide is administered at a dose of 110 mg.
46 . The method of claim 43 , wherein the modified oligonucleotide is administered at a dose of 110 mg.
47 . The method of claim 44 , wherein the modified oligonucleotide is administered at a dose of 110 mg.
48 . A method of treating Alport Syndrome comprising administering to a subject having or suspected of having Alport Syndrome 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), wherein nucleosides not followed by a subscript are β-D-deoxyribonucleosides, nucleosides followed by a subscript “E” are 2′-O-methoxyethyl (2′MOE) nucleosides, nucleosides followed by a subscript “S” are S-cEt nucleosides, and each internucleoside linkage is a phosphorothioate internucleoside linkage; and wherein the modified oligonucleotide is administered at a dose of 110 mg.
49 . The method of claim 48 , wherein the subject has been diagnosed as having Alport Syndrome prior to administering the pharmaceutical composition.
50 . The method of claim 48 , wherein the Alport Syndrome is the X-linked form of Alport Syndrome or the autosomal form of Alport Syndrome.
51 - 60 . (canceled)