Methods for treatment of polycystic kidney disease

Patent metadata

Field	Value
Publication number	US-10633657-B2
Application number	US-201615753865-A
Country	US
Kind code	B2
Filing date	Aug 25, 2016
Priority date	Aug 26, 2015
Publication date	Apr 28, 2020
Grant date	Apr 28, 2020

Abstract

Provided herein are methods for the treatment of poly-cystic kidney disease, including autosomal dominant polycystic kidney disease, using modified oligonucleotides targeted to miR-17.

First claim

What is claimed is:

1. A method of treating polycystic kidney disease comprising administering to a subject in need thereof a compound comprising a modified oligonucleotide consisting of 8 to 25 linked nucleosides, wherein the modified oligonucleotide comprises at least one modified nucleoside, and wherein the nucleobase sequence of the modified oligonucleotide is complementary to miR-17 and comprises the nucleobase sequence 5′-GCACTTTG-3′ (SEQ ID NO: 3), wherein each T in the nucleobase sequence is independently selected from a T and a U.

2. The method of claim 1 , wherein the subject has polycystic kidney disease or is suspected of having polycystic kidney disease.

3. The method of claim 1 wherein the subject has been diagnosed as having polycystic kidney disease prior to administering the modified oligonucleotide.

4. The method of claim 1 , wherein the polycystic kidney disease is autosomal recessive polycystic kidney disease or autosomal dominant polycystic kidney disease.

5. The method of claim 1 , wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease.

6. The method of claim 1 , wherein the subject has increased total kidney volume.

7. The method of claim 1 , wherein the subject has hypertension.

8. The method of claim 1 , wherein the administering:
a) improves kidney function in the subject;
b) delays the worsening of kidney function in the subject;
c) reduces total kidney volume in the subject;
d) slows the increase in total kidney volume in the subject;
e) inhibits cyst growth in the subject;
f) slows the increase in cyst growth in the subject;
g) reduces kidney pain in the subject;
h) slows the increase in kidney pain in the subject;
i) delays the onset of kidney pain in the subject;
j) reduces hypertension in the subject;
k) slows the worsening of hypertension in the subject;
l) delays the onset of hypertension in the subject;
m) reduces fibrosis in the kidney of the subject;
n) slows the worsening of fibrosis in the kidney of the subject;
o) delays the onset of end stage renal disease in the subject;
p) delays time to dialysis for the subject;
q) delays time to renal transplant for the subject; and/or
r) improves life expectancy of the subject.

9. The method of claim 1 , wherein the administering:
a) reduces albuminuria in the subject;
b) slows the worsening of albuminuria in the subject;
c) delays the onset of albuminuria in the subject;
d) reduces hematuria in the subject;
e) slows the worsening of hematuria in the subject;
f) delays the onset of hematuria in the subject;
g) reduces blood urea nitrogen in the subject;
h) reduces creatinine in the blood of the subject;
i) improves creatinine clearance in the subject;
j) reduces albumin:creatinine ratio in the subject;
k) improves glomerular filtration rate in the subject;
l) slows the worsening of glomerular filtration rate in the subject;
m) reduces neutrophil gelatinase-associated lipocalin (NGAL) protein in the urine of the subject; and/or
n) reduces kidney injury molecule-1 (KIM-1) protein in the urine of the subject.

10. The method of claim 6 , wherein the total kidney volume is height-adjusted kidney volume.

11. The method of claim 1 , comprising administering at least one additional therapy that is an anti-hypertensive agent.

12. 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), 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, dialysis, and kidney transplant.

13. The method of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary, is at least 95% complementary, or is 100% complementary to the nucleobase sequence of miR-17 (SEQ ID NO: 1).

14. The method of claim 1 , wherein the modified oligonucleotide consists of 8, 9, 10, 11 or 12 linked nucleosides.

15. The method of claim 1 , wherein the modified oligonucleotide consists of 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 linked nucleosides.

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

17. The method of claim 1 , wherein the modified nucleoside is selected from an S-cEt nucleoside, a 2′-O-methoxyethyl nucleoside, and an LNA nucleoside.

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

19. The method of claim 1 , wherein the compound consists of the modified oligonucleotide.

20. The method of claim 1 , comprising administering a therapeutically effective amount of the compound.

Assignees

• Regulus Therapeutics Inc
• Univ Texas

Inventors

• Androsavich John R
• Chau B Nelson
• Patel Vishal D

Classifications

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• A61P9/12

  Antihypertensives · CPC title

• C12N2310/315

  Phosphorothioates · CPC title

• C12N2310/113

  targeting other non-coding nucleic acids, e.g. antagomirs · CPC title

• C12N2310/322

  2'-R Modification · CPC title