Therapeutic Targets in Polycystic Liver Disease.
Polycystic liver diseases (PLD) are a group of genetic disorders initiated by mutations in several PLD-related genes and characterized by the presence of multiple cholangiocyte-derived hepatic cysts that progressively replace liver tissue. PLD co-exists with Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Autosomal Recessive PKD as well as occurs alone (i.e., Autosomal Dominant Polycystic Liver Disease [ADPLD]). PLD associated with ADPKD and ARPKD belong to a group of disorders known as cholangiociliopathies since many disease-causative and disease-related proteins are expressed in primary cilia of cholangiocytes. Aberrant expression of these proteins in primary cilia affects their structures and functions promoting cystogenesis. Current medical therapies for PLD include symptomatic management and surgical interventions. To date, the only available drug treatment for PLD patients that halt disease progression and improve quality of life are somatostatin analogs. However, the modest clinical benefits, need for long-term maintenance therapy, and the high cost of treatment justify the necessity for more effective treatment options. Substantial evidence suggests that experimental manipulations with components of the signaling pathways that influence cyst development (e.g., cAMP, intracellular calcium, receptor tyrosine kinase, transient receptor potential cation channel subfamily V member 4 (TRPV4) channel, mechanistic target of rapamycin (mTOR), histone deacetylase (HDAC6), Cdc25A phosphatase, miRNAs and metalloproteinases) attenuate growth of hepatic cysts. Many of these targets have been evaluated in pre-clinical trials suggesting their value as potential new therapies. This review outlines the current clinical and preclinical treatment strategies for PLD.
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States.
Tatyana V
TV
Masyuk
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States.
Anatoliy I
AI
Masyuk
Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street, SW Rochester, Minnesota, MN 55905, United States.
Nicholas F
NF
LaRusso
D000818:Animals; D001343:Autophagy / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002986:Clinical Trials as Topic; D003560:Cysts / Q000188:drug therapy* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D053263:Gene Regulatory Networks / Q000187:drug effects*; D006801:Humans; D008107:Liver Diseases / Q000188:drug therapy* / Q000378:metabolism; D058990:Molecular Targeted Therapy / Q000379:methods*; D011788:Quality of Life; D015398:Signal Transduction / Q000187:drug effects; D013004:Somatostatin / Q000031:analogs & derivatives
D013004:Somatostatin
Cholangiocytes; cholangiociliopathies; cilia; hepatic cystogenesis; polycystic liver disease; therapies