Treatment of polycystic diseases with an HDAC6 inhibitor
Inventors
Gradilone, Sergio A. • LaRusso, Nicholas F.
Assignees
Mayo Foundation for Medical Education and Research • National Institutes of Health NIH
Publication Number
US-10660890-B2
Publication Date
2020-05-26
Expiration Date
2034-10-24
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Abstract
An HDAC6-specific inhibitor (i.e., a compound of Formula I or II) is shown to reduce the pathogenesis associated with polycystic disease. Administration of an HDAC6-specific inhibitor attenuated many of the symptoms characteristic of polycystic liver disease including cyst formation, cyst growth and cholangiocyte proliferation. Treatment with a HDAC6-specific inhibitor also increased the amount of bile duct acetylated tubulin and β-catenin phosphorylation and/or acetylation while reducing bile duct β-catenin synthesis. These results demonstrate that HDAC6 is overexpressed in cystic cholangiocytes and that its pharmacological inhibition reduces cholangiocyte proliferation and cyst growth.
Core Innovation
The invention provides methods of treating polycystic disease by administering a therapeutically effective amount of a histone deacetylase 6 (HDAC6) specific inhibitor compound of Formula I or II. These HDAC6-specific inhibitors reduce cyst growth, cholangiocyte proliferation, and other symptoms characteristic of polycystic liver disease and renal cystic diseases. Treatment with these inhibitors also increases bile duct acetylated tubulin and β-catenin phosphorylation and/or acetylation while reducing bile duct β-catenin synthesis.
The problem addressed is that HDAC6 is overexpressed in cystic cholangiocytes and plays a key role in the pathogenesis of polycystic diseases, including hepatic and renal cyst formation and growth. Current understanding of HDAC6's function in microtubule dynamics, cell migration, and cell-cell interactions suggested that its dysregulation contributes to the proliferation of cystic cholangiocytes and cyst growth. Thus, there was a need for specific HDAC6 inhibitors to modulate these pathological processes and provide effective treatment for polycystic diseases.
Claims Coverage
The claims cover a method of treating polycystic disease by administering an HDAC6-specific inhibitor with various specific therapeutic effects and disease types. Six main inventive features are identified based on the independent claims provided.
Method for treating polycystic disease with an HDAC6-specific inhibitor
Administering to a subject a therapeutically effective amount of a histone deacetylase 6 specific inhibitor, where the inhibitor is a compound of Formula I or II or pharmaceutically acceptable salts thereof, to treat polycystic disease.
Reduction of cyst growth by HDAC6 inhibition
Using an amount of the HDAC6-specific inhibitor compound effective at reducing cyst growth in the subject with polycystic disease.
Treatment of renal cystic diseases including polycystic kidney disease
Applying the HDAC6-specific inhibitor to polycystic disease where the disease is renal cystic disease, including autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).
Prevention of cyst formation through HDAC6 inhibition
Employing a therapeutically effective amount of the HDAC6-specific inhibitor compound effective at preventing formation of cysts in subjects predisposed to polycystic disease.
Inhibition of cholangiocyte proliferation and modulation of bile duct biomarkers
The amount of HDAC6-specific inhibitor compound is effective at inhibiting cholangiocyte proliferation, increasing bile duct acetylated tubulin, reducing bile duct β-catenin synthesis, and increasing bile duct β-catenin phosphorylation and/or acetylation.
Inhibition of cyst growth and cholangiocyte proliferation by HDAC6-specific compounds
Administering HDAC6-specific inhibitor compound in amounts effective at inhibiting cholangiocyte proliferation and cyst growth in subjects with polycystic disease.
The claims comprehensively cover the use of specific HDAC6 inhibitors for treating polycystic diseases by reducing cyst growth, preventing cyst formation, inhibiting cholangiocyte proliferation, modulating bile duct acetylated tubulin and β-catenin, and addressing renal cystic conditions including ADPKD and ARPKD.
Stated Advantages
HDAC6-specific inhibitors reduce numerous pathological hallmarks of polycystic liver disease including hepatomegaly and cyst growth in liver and kidney.
Treatment with HDAC6-specific inhibitors prevents cyst formation in genetically predisposed subjects.
Pharmacological inhibition of HDAC6 effectively inhibits cholangiocyte proliferation and modulates β-catenin signaling involved in cystogenesis.
HDAC6-specific inhibitors demonstrate selective reduction of cyst growth without affecting normal cells significantly.
Documented Applications
Treatment of polycystic liver disease (PLD), including cases occurring alone or in conjunction with polycystic kidney disease (PKD).
Treatment of renal cystic diseases such as polycystic kidney disease, including autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).
Treatment of genetic polycystic diseases caused by mutations in genes such as PRKCSH, Sec63, Pkd1, Pkd2, and Pkhd1.
Use of HDAC6-specific inhibitors to inhibit cholangiocyte proliferation, reduce cyst growth, and modulate molecular markers such as bile duct acetylated tubulin and β-catenin in affected subjects.
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