Treatment of polycystic diseases with an HDAC6 inhibitor
Inventors
Gradilone, Sergio A. • LaRusso, Nicholas F.
Assignees
National Institutes of Health NIH
Publication Number
US-11666569-B2
Publication Date
2023-06-06
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
This invention provides methods for treating polycystic disease by administering a therapeutically effective amount of histone deacetylase 6 (HDAC6) specific inhibitor compounds of Formula I or II. The HDAC6-specific inhibitors reduce the pathogenesis associated with polycystic disease by attenuating symptoms such as cyst formation, cyst growth, and cholangiocyte proliferation. The inhibitors increase bile duct acetylated tubulin and β-catenin phosphorylation and/or acetylation while decreasing bile duct β-catenin synthesis.
The problem addressed is that polycystic diseases, such as polycystic liver disease and polycystic kidney disease, involve cystic growth and cholangiocyte proliferation with HDAC6 being overexpressed in cystic cholangiocytes. Current treatments do not adequately target this molecular mechanism. HDAC6 uniquely modulates microtubule dynamics and cell proliferation via deacetylation of non-histone proteins, and its overexpression contributes to cyst growth.
The invention thereby solves the problem of excessive cyst growth and cholangiocyte proliferation in polycystic diseases by selectively inhibiting HDAC6, reducing β-catenin signaling and cell proliferation leading to decreased cystogenesis. The methods include administering compounds of specified chemical formulas that have potent and selective HDAC6 inhibitory activity, demonstrated to effectively reduce cyst formation and growth both in vitro and in vivo in relevant animal models and human cells.
Claims Coverage
The patent contains one independent claim encompassing a method of treating polycystic disease by administering a therapeutically effective amount of specific HDAC6 inhibitor compounds.
Method of treating polycystic disease using specific HDAC6 inhibitors
Administering to a subject with polycystic disease a therapeutically effective amount of histone deacetylase 6 (HDAC6) specific inhibitor compounds selected from the described chemical structures (Formula I and II).
Effective reduction of cyst growth
Use of an amount of HDAC6 specific inhibitor compound effective at reducing cyst growth in the subject.
Use in specific polycystic diseases and locations
Treatment method applies to polycystic liver disease and renal cystic disease including polycystic kidney disease, with cysts located in the liver and/or kidney.
Prevention of cyst formation and inhibition of cell proliferation
The HDAC6 inhibitor amount is effective at preventing cyst formation and inhibiting cholangiocyte proliferation.
Modulation of bile duct molecular markers
Treatment increases bile duct acetylated tubulin and β-catenin phosphorylation and/or acetylation, while reducing bile duct β-catenin synthesis.
The independent claim covers a method for treating polycystic diseases by administering specific HDAC6 inhibitor compounds in effective amounts to reduce cyst growth, inhibit cholangiocyte proliferation, prevent cyst formation, and modulate bile duct molecular markers, applicable to liver and kidney cystic conditions.
Stated Advantages
HDAC6 inhibition decreases cholangiocyte proliferation and cyst growth, addressing a key pathological feature of polycystic diseases.
The treatment reduces hepatomegaly and fibrosis associated with polycystic liver disease, demonstrating disease modification.
Selective HDAC6 inhibitors increase acetylation of tubulin and β-catenin phosphorylation, leading to destabilization and degradation of β-catenin protein involved in cystogenesis.
The compounds demonstrate efficacy both in vitro and in vivo models, including genetic models orthologous to human disease, supporting therapeutic potential.
Documented Applications
Treatment of polycystic liver disease (PLD), including genetic forms such as those caused by PRKCSH and Sec63 mutations.
Treatment of renal cystic diseases including polycystic kidney disease (PKD), autosomal dominant polycystic kidney disease (ADPKD) caused by mutations in Pkd1 and Pkd2 genes, and autosomal recessive polycystic kidney disease (ARPKD) caused by Pkhd1 gene mutations.
Use in subjects genetically predisposed to polycystic diseases to prevent cyst formation.
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