Targeting cGMP-related phosphodiesterases to reduce cyst formation in cystic kidney disease, and related materials and methods
Inventors
Bacallao, Robert • Glazier, James A. • Clendenon, Sherry G. • Cunha De Almeida, Rita Maria
Assignees
Pkd Advances LLC • Indiana University Research and Technology Corp • US Department of Veterans Affairs
Publication Number
US-10456404-B2
Publication Date
2019-10-29
Expiration Date
2036-03-14
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Described herein is the identification of cGMP-specific phosphodiesterase upregulation in cystic kidney diseases. Also described is the use of cGMP-specific phosphodiesterase inhibitors for preventing the progression and/or treatment of cystic kidney diseases. Other aspects described provide medicaments for preventing the progression and/or treating cystic kidney diseases, and methods of diagnosing cystic kidney disease.
Core Innovation
The invention identifies the upregulation of cGMP-specific phosphodiesterases (PDEs) — specifically PDE types 5, 6, and 9 — in cystic kidney diseases including autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease. This discovery provides a novel molecular target for these diseases, which previously lacked clarity in the mechanisms underlying cyst formation despite knowing many causative genes.
The invention further discloses the use of phosphodiesterase inhibitors targeting PDE5, PDE6, and PDE9 to prevent the progression and/or treat cystic kidney diseases. Methods of preventing cyst growth by administering these inhibitors, medicaments comprising such inhibitors (optionally with kidney-specific delivery systems), and diagnostic methods measuring PDE gene expression levels to identify cystic kidney disease are also described.
Claims Coverage
The patent discloses a total of two independent claims covering methods and diagnostic techniques, with additional dependent claims refining these methods and medicament compositions. The inventive features focus on PDE inhibitors targeting PDE5, PDE6, and PDE9 for treatment and diagnosis of cystic kidney disease.
Method of preventing progression and/or treating cystic kidney disease using specific phosphodiesterase inhibitors
A method comprising administering an effective amount of at least one phosphodiesterase inhibitor, pharmaceutically effective prodrug, or active metabolite that individually inhibits phosphodiesterase type 5, 6, or 9 to a subject in need to prevent progression or treat cystic kidney disease.
Use of specific compounds as phosphodiesterase inhibitors for treatment
Administering effective amounts of compounds individually selected from sildenafil, aildenafil, tadalafil, vardenafil, udenafil, avanafil, lodenafil, mirodenafil, dipyridamole, icariin, zaprinast, PF-04447943, BAY 73-6691 or their pharmaceutically acceptable salts, hydrates, prodrugs, or active metabolites for preventing progression or treating cystic kidney disease.
Method for diagnosing cystic kidney disease by measuring PDE expression levels
A method comprising measuring expression levels of at least one gene product of cGMP-related phosphodiesterase genes selected from PDE5, PDE6, and PDE9 in a renal test sample from a subject, comparing these levels against control expression values, and diagnosing cystic kidney disease if elevated expression levels are detected.
The claims collectively cover methods of treating cystic kidney diseases through administration of PDE5, PDE6, or PDE9 inhibitors, use of particular known PDE inhibitors and their derivatives for this purpose, drug delivery system implementations, and methods of diagnosing cystic kidney diseases by measuring elevated PDE gene expression.
Stated Advantages
Use of cGMP-specific phosphodiesterase inhibitors reduces average renal cyst size and prevents renal cyst growth in cystic kidney diseases.
The treatment inhibits formation of large cysts, thereby slowing progression of polycystic kidney disease effectively, beyond a mere small reduction in cyst size.
Lower drug concentrations are effective, consistent with serum levels achieved by approved dosing of sildenafil for other indications.
Documented Applications
Prevention of progression and treatment of cystic kidney diseases, including autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease, in humans and various animals.
Use of PDE inhibitors as medicaments optionally combined with kidney-targeted drug delivery systems such as lysozyme, chitosan, nanoparticles, or liposomes.
Diagnostic methods for cystic kidney disease by measuring expression levels of PDE5, PDE6, and PDE9 in renal cell or tissue samples compared to healthy controls.
Interested in licensing this patent?