Methods for treatment of polycystic kidney disease
Inventors
Androsavich, John R. • Chau, B. Nelson • Patel, Vishal D.
Assignees
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Publication Number
US-11168325-B2
Publication Date
2021-11-09
Expiration Date
Abstract
Provided herein are methods for the treatment of polycystic kidney disease, including autosomal dominant polycystic kidney disease, using modified oligonucleotides targeted to miR-17.
Core Innovation
The invention relates to treatment of autosomal dominant polycystic kidney disease by administering to a subject in need thereof a compound consisting of a modified oligonucleotide consisting of 8 to 25 linked nucleosides. The modified oligonucleotide is complementary to miR-17, and the nucleobase sequence comprises 5b9-GCACTTTG-3b9 (SEQ ID NO: 3), with each T independently selected from a T and a U.
The disclosed approach further addresses subject conditions and clinical/diagnostic contexts, including increased miR-17 levels, increased total kidney volume (TKV) or height-adjusted total kidney volume (HtTKV), hypertension, and impaired kidney function, including progression toward end-stage renal disease (ESRD), dialysis, or kidney transplant. The described treatment outcomes include reduced kidney volume and/or cyst growth and improvements in kidney function markers such as blood urea nitrogen (BUN), creatinine, creatinine clearance, and GFR/eGFR.
The disclosure includes miR-17 family targeting and cross-reactivity concepts, including miR-20a, miR-20b, miR-93, miR-106a, and miR-106b. It also includes characterization of the modified oligonucleotide and its chemistry, including modified nucleosides and a phosphorothioate internucleoside linkage.
Claims Coverage
The document provides one independent claim directed to treating autosomal dominant polycystic kidney disease using a compound consisting solely of a modified oligonucleotide complementary to miR-17 and containing SEQ ID NO: 3, with T independently selected as T or U; dependent claims further refine the oligonucleotide and subject characteristics by adding quantitative complementarity, specifying particular modified nucleoside types and linkage types, and characterizing the subject condition.
MiR-17-complementary modified oligonucleotide for ADPKD treatment
A method of treating polycystic kidney disease comprising administering to a subject in need thereof a compound consisting of a modified oligonucleotide consisting of 8 to 25 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is complementary to miR-17, wherein the nucleobase sequence comprises 5b9-GCACTTTG-3b9 (SEQ ID NO: 3), wherein each T in the nucleobase sequence is independently selected from a T and a U, and wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease.
MiR-17 complementarity threshold
The nucleobase sequence of the modified oligonucleotide is at least 90% complementary, at least 95% complementary, or at least 100% complementary to the nucleobase sequence of miR-17 (SEQ ID NO: 1).
Phosphorothioate internucleoside linkage
The modified internucleoside linkage is a phosphorothioate internucleoside linkage.
Specified modified nucleoside types
The modified nucleoside is selected from an S-cEt nucleoside, a 2b9-O-methoxyethyl nucleoside, or an LNA nucleoside.
Subject characterization by increased total kidney volume
The subject shows increased total kidney volume.
Overall, the claim set centers on administering a compound consisting of a specific 8 to 25 linked-nucleoside modified oligonucleotide that is complementary to miR-17 and includes SEQ ID NO: 3 with each T independently selected as T or U, for autosomal dominant polycystic kidney disease, with dependent refinements specifying complementarity thresholds, particular modified nucleoside chemistries, phosphorothioate linkage, and certain subject characteristics.
Stated Advantages
Reduced kidney volume and/or cyst growth.
Improved kidney function markers including BUN, creatinine, creatinine clearance, and GFR/eGFR.
Reduced fibrosis.
Reduced albuminuria and hematuria.
Reduced biomarkers NGAL and KIM-1.
Documented Applications
Treating autosomal dominant polycystic kidney disease in a subject in need thereof by administering a modified oligonucleotide complementary to miR-17.
Use in clinical/diagnostic contexts involving increased miR-17 levels, increased total kidney volume (TKV) or height-adjusted total kidney volume (HtTKV), hypertension, and impaired kidney function, including progression toward ESRD, dialysis, or kidney transplant.
Experimental application: anti-miR-17 reduction of kidney weight/cystic index and injury biomarkers in a Pkhd1/cre;Pkd2F/F mouse ADPKD model.
Experimental application: anti-miR-17 reduces disease measures in a Pcy mouse model.
Experimental application: anti-miR-17 inhibits proliferation and cyst formation in primary human ADPKD cyst epithelial cultures.
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