Methods and Compositions for Treatment of Polycystic Kidney Disease

1 . A compound comprising a modified oligonucleotide, wherein the modified oligonucleotide has the following structure in the 5′ to 3′ orientation:

(N″) p —(N) r —(N′) q

wherein each N″ is, independently, a modified or unmodified nucleoside;

p is from 0 to 14; wherein if p is not 0, the nucleobase sequence of (N″) p is complementary to an equal-length portion of the nucleobase sequence of miR-17;

each N of (N) r is, independently, a modified or unmodified nucleotide, and the nucleobase sequence of (N) r is 5′-AGCACUUU-3′;

N′ is a nucleoside comprising a modified sugar moiety;

q is 0 or 1; wherein if q is 1, the nucleobase of N′ is a uracil nucleobase, a cytosine nucleobase, or a purine nucleobase, provided that the purine nucleobase does not have a hydrogen bond acceptor at position 6; and

each cytosine is independently selected from a non-methylated cytosine and a 5-methylcytosine;

or a pharmaceutically acceptable salt thereof.

2 . The compound of claim 1 , wherein the structure of (N) r is:

A S G S C M A F C F U F U M U S

wherein nucleosides followed by subscript “M” are 2′-O-methyl nucleosides;

nucleosides followed by subscript “F” are 2′-fluoro nucleosides; and

nucleosides followed by subscript “S” are S-cEt nucleosides.

3 . The compound of claim 1 , wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage, or wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

4 . (canceled)

5 . (canceled)

6 . (canceled)

7 . (canceled)

8 . The compound of claim 1 , wherein p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, and wherein:

(a) the nucleobase sequence of (N″) p has no more than one mismatch to the nucleobase sequence of miR-17 (SEQ ID NO: 1); or

(b) the nucleobase sequence of (N″) p has no mismatches to the nucleobase sequence of miR-17 (SEQ ID NO: 1); or

(c) the nucleobase sequence of (N″) p is selected from CUACCUGCACUGUA (SEQ ID NO: 7), CUACCUGCACUGU (SEQ ID NO: 8), CUACCUGCACUG (SEQ ID NO: 9), CUACCUGCACU (SEQ ID NO: 10), CUACCUGCAC (SEQ ID NO: 11), CUACCUGCA, CUACCUGC, CUACCUG, CUACCU, CUACC, CUAC, CUA, CU, and C.

9 . (canceled)

10 . (canceled)

11 . (canceled)

12 . The compound of claim 1 , wherein the nucleobase of N′ is a purine nucleobase that does not have a hydrogen bond acceptor at position 6.

13 . The compound of claim 12 , wherein the nucleobase of N′ is selected from adenosine, 2-aminopurine, 2,6-diaminopurine, and isoguanosine.

14 . The compound of claim 1 , wherein the sugar moiety of N′ is not a 2′-O-methyl sugar, or the sugar moiety of N′ is a 2′-O-methoxyethyl sugar or an S-cEt sugar.

15 . (canceled)

16 . The compound of claim 1 , wherein the structure of the modified oligonucleotide is 5′-A S G S C M A F C F U F U M U S A S -3′, or 5′-A S G S C M A F C F U F U M U S U S -3′, or 5′-A S G S C M A F C F U F U M U S C S -3′, or 5′-A S G S C M A F C F U F U M U S -3′, wherein each cytosine is a non-methylated cytosine.

17 . (canceled)

18 . (canceled)

19 . (canceled)

20 . (canceled)

21 . (canceled)

22 . A modified oligonucleotide having the structure:

wherein B is a uridine nucleobase, a cytosine nucleobase, or a purine nucleobase, provided that the purine nucleobase does not have a hydrogen bond acceptor at position 6, or wherein B is selected from adenosine 2-aminopurine, 2,6-diaminopurine, and isoguanosine; or a pharmaceutically acceptable salt thereof.

23 . (canceled)

24 . The modified oligonucleotide of claim 22 , wherein the pharmaceutically acceptable salt is a sodium salt.

25 . (canceled)

26 . (canceled)

27 . A modified oligonucleotide having the structure:

or a pharmaceutically acceptable salt thereof.

28 . The modified oligonucleotide of claim 27 , wherein the pharmaceutically acceptable salt is a sodium salt.

29 . A modified oligonucleotide having the structure:

30 . A pharmaceutical composition comprising a compound of claim 27 and a pharmaceutically acceptable diluent.

31 . (canceled)

32 . The pharmaceutical composition of claim 30 , wherein the pharmaceutically acceptable diluent is a saline solution.

33 . A pharmaceutical composition comprising a compound of claim 27 , which is a lyophilized composition.

34 . A pharmaceutical composition consisting essentially of a compound of claim 27 in a saline solution.

35 . A method for inhibiting the activity of one or more members of the miR-17 family in a cell, comprising contacting the cell with a compound of claim 1 .

36 . A method for inhibiting the activity of one or more members of the miR-17 family in a subject, comprising administering to the subject a compound of claim 1 or a pharmaceutical composition comprising the compound.

37 . (canceled)

38 . A method of treating polycystic kidney disease comprising administering to a subject in need thereof a compound of claim 1 , or a pharmaceutical composition comprising the compound.

39 .- 58 . (canceled)

59 . A method of treating polycystic kidney disease comprising administering to a subject in need thereof the modified oligonucleotide of claim 27

or a pharmaceutically acceptable salt thereof.

60 . The method of claim 59 , wherein pharmaceutically acceptable salt is a sodium salt.

61 .- 67 . (canceled)

68 . The method of claim 59 , wherein (a) the subject has polycystic kidney disease; (b) the subject is suspected of having polycystic kidney disease; (c) the subject has been diagnosed as having polycystic kidney disease using clinical, histopathologic, and/or genetic criteria; and/or (d) the subject, prior to administration of the compound or pharmaceutical composition, was determined to have a decreased level of polycystin-1 (PC1) and/or polycystin-2 (PC2) in the kidney, urine or blood of the subject.

69 . (canceled)

70 . (canceled)

71 . (canceled)

72 . The method of claim 59 , wherein the polycystic kidney disease is autosomal recessive polycystic kidney disease or autosomal dominant polycystic kidney disease.

73 . (canceled)

74 . The method of claim 59 , wherein (a) the subject has a mutation selected from a mutation in the PKD1 gene or a mutation in the PKD2 gene; (b) the subject has increased total kidney volume; (c) the subject has hypertension; and/or (d) the subject has impaired kidney function.

75 . (canceled)

76 . (canceled)

77 . (canceled)

78 . The method of claim 59 , wherein the administering (a) reduces total kidney volume in the subject; (b) slows the rate of increase of total kidney volume in the subject, optionally wherein the total kidney volume is height-adjusted total kidney volume; (c) slows the rate of decline of glomerular filtration rate in the subject; (d) increases glomerular filtration rate in the subject, optionally wherein the glomerular filtration rate is estimated glomerular filtration rate; and/or (e) slows the increase in the growth of cysts in the kidney and/or liver of the subject.

79 .- 84 . (canceled)

85 . The method of claim 59 , wherein the administering:

a) improves kidney function in the subject;

b) delays the worsening of kidney function in the subject;

c) reduces kidney pain in the subject;

d) slows the increase in kidney pain in the subject;

e) delays the onset of kidney pain in the subject;

f) reduces hypertension in the subject;

g) slows the worsening of hypertension in the subject;

h) delays the onset of hypertension in the subject;

i) reduces fibrosis in the kidney of the subject;

j) slows the worsening of fibrosis in the kidney of the subject;

k) delays the onset of end stage renal disease in the subject;

l) delays time to dialysis for the subject;

m) delays time to renal transplant for the subject;

n) improves life expectancy of the subject;

o) reduces albuminuria in the subject;

p) slows the worsening of albuminuria in the subject;

q) delays the onset of albuminuria in the subject;

r) reduces hematuria in the subject;

s) slows the worsening of hematuria in the subject;

t) delays the onset of hematuria in the subject;

u) reduces blood urea nitrogen level in the subject;

v) reduces serum creatinine level in the subject;

w) improves creatinine clearance in the subject;

x) reduces albumin:creatinine ratio in the subject;

y) increases polycystin-1 (PC1) in the urine of the subject;

z) increases polycystin-2 (PC2) in the urine of the subject;

aa) reduces neutrophil gelatinase-associated lipocalin (NGAL) protein in the urine of the subject; and/or

bb) reduces kidney injury molecule-1 (KIM-1) protein in the urine of the subject.

86 . (canceled)

87 . The method of claim 59 , comprising:

a) measuring total kidney volume in the subject;

b) measuring hypertension in the subject;

c) measuring kidney pain in the subject;

d) measuring polycystin-1 (PC1) in the urine of the subject;

e) measuring polycystin-2 (PC2) in the urine of the subject;

f) measuring fibrosis in the kidney of the subject;

g) measuring blood urea nitrogen level in the subject;

h) measuring serum creatinine level in the subject;

i) measuring creatinine clearance in the subject;

j) measuring albuminuria in the subject;

k) measuring albumin:creatinine ratio in the subject;

l) measuring glomerular filtration rate in the subject;

m) measuring neutrophil gelatinase-associated lipocalin (NGAL) protein in the urine of the subject; and/or

n) measuring kidney injury molecule-1 (KIM-1) protein in the urine of the subject.

88 . The method of claim 59 , comprising administering at least one additional therapy, wherein at least one additional therapy is an anti-hypertensive agent; or wherein at least one additional therapy is 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, a glucosylceramide synthase inhibitor, an antihyperglycermic agent, dialysis, and kidney transplant.

89 . (canceled)

90 . The method of claim 88 , wherein the angiotensin II converting enzyme (ACE) inhibitor is selected from captopril, enalapril, lisinopril, benazepril, quinapril, fosinopril, and ramipril; the angiotensin II receptor blocker (ARB) is selected from candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, and eprosartan; the vasopressin receptor 2 antagonist is tolvaptan; the aldosterone receptor antagonist is spironolactone; the kinase inhibitor is selected from bosutinib and KD019; the mTOR inhibitor is selected from everolimus, rapamycin, and sirolimus; the hormone analogue is selected from somatostatin and adrenocorticotrophic hormone; the glucosylceramide synthase inhibitor is venglustat; and the antihyperglycemic agent is metformin.

91 .- 99 . (canceled)

100 . The method of claim 59 , wherein the subject is a human subject.

101 .- 105 . (canceled)