Methods and compositions for treating liver disease
Inventors
Alpini, Gianfranco • Glaser, Shannon • Meng, Fanyin
Assignees
US Department of Veterans Affairs
Publication Number
US-11318190-B2
Publication Date
2022-05-03
Expiration Date
2038-04-05
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Abstract
Disclosed is a method of modulating the Sct/SR axis in a mammalian subject in need thereof, including in a subject suffering from a liver disease, such as but not limited to, Early Stage PBC, Primary Sclerosing Cholangitis, Primary Biliary Cholangitis, Biliary Altresia, NASH, NAFLD, or Alcohol induced liver injury. A method of treating Late Stage PBC in a mammalian subject in need thereof is also disclosed; further disclosed is a method of ameliorating PBC-induced biliary damage in a mammalian subject in need thereof. Pharmaceutical compositions for modulating the Sct/SR axis, comprising a SR antagonist or a SR agonist, and a pharmaceutically acceptable carrier or excipient are also disclosed.
Core Innovation
The invention discloses methods of modulating the secretin/secretin receptor (Sct/SR) axis in mammalian subjects to treat liver diseases. Specifically, it includes administering an effective amount of an SR antagonist to treat early stage liver diseases such as early stage Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis, Biliary Atresia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and alcohol-induced liver injury. Furthermore, the invention provides a method of treating late stage PBC by administration of an SR agonist, including secretin or its variants, which can ameliorate biliary damage and liver fibrosis associated with PBC.
The problem addressed by the invention is the need for effective treatment modalities for liver diseases such as PBC, NAFLD, NASH, and alcoholic liver disease (ALD), conditions characterized by biliary damage, cholangiocyte proliferation or apoptosis, liver fibrosis, and cirrhosis. Existing treatments like ursodeoxycholic acid (UDCA) are ineffective in many patients, especially in later stages of PBC, with limited benefit on mortality. The secretin/secretin receptor signaling pathway plays a prominent role in regulating biliary homeostasis, proliferation, apoptosis, senescence, and hepatic fibrosis, but its modulation as a therapeutic approach has not been adequately explored.
The invention is based on experimental observations including that the Sct/SR axis is upregulated in cholangiocytes from animal models and human patients with liver disease, that modulation of this axis affects biliary proliferation, apoptosis, senescence, hepatic fibrosis, and stellate cell activation, and that the use of SR antagonists or agonists can respectively reduce or increase these parameters depending on disease stage. Pharmaceutical compositions comprising SR antagonists or agonists and pharmaceutically acceptable carriers are also disclosed.
Claims Coverage
The patent sets forth two independent claims covering methods of treating early and late stage cholestatic liver diseases by modulating the Sct/SR axis.
Treatment of early stage cholestatic liver disease with Sec 5-27
Administering an effective amount of Sec 5-27 (an SR antagonist) to treat early stage diseases including Primary Biliary Cholangitis (PBC), Biliary Atresia, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and alcohol induced liver injury, with inhibition of bile duct cell proliferation.
Treatment of late stage Primary Biliary Cholangitis with secretin
Administering an effective amount of secretin (an SR agonist) as a single active agent to treat late stage PBC (Stage III or IV, or with bilirubin levels >1 mg/dl), ameliorating PBC-induced biliary damage and liver fibrosis.
The claims cover methods of treating liver diseases by modulating the Sct/SR axis, specifically using SR antagonists for early stage diseases and SR agonists for late stage PBC, focusing on regulating biliary proliferation, hepatic fibrosis, and biliary damage.
Stated Advantages
Modulating the Sct/SR axis can reduce liver damage, biliary proliferation, and hepatic fibrosis in early stage PBC.
Administration of secretin or SR agonists in late stage PBC can restore biliary mass and ameliorate liver damage and fibrosis.
Targeting the Sct/SR axis affects cholangiocyte apoptosis and senescence, thereby influencing disease progression.
SR knockout or antagonism reduces hepatic steatosis and fibrosis in animal models of NAFLD and alcoholic liver disease.
Documented Applications
Treatment of early stage cholestatic liver diseases including Primary Biliary Cholangitis (stages I and II), Biliary Atresia, NASH, NAFLD, and alcohol induced liver injury by administering SR antagonists such as Sec 5-27.
Treatment of late stage Primary Biliary Cholangitis (stages III and IV) by administering secretin or other SR agonists to ameliorate biliary damage and liver fibrosis.
Use of modulation of the Sct/SR axis to reduce biliary proliferation, hepatic fibrosis, cholangiocyte apoptosis, and senescence in rodent models of PBC, PSC, NAFLD/NASH, and alcoholic liver disease.
Pharmaceutical compositions comprising SR antagonists or agonists formulated with pharmaceutically acceptable carriers for various administration routes to treat liver diseases.
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