Therapeutic Targets in Polycystic Liver Disease

Abstract

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.

Evidence for a “Pathogenic Triumvirate” in Congenital Hepatic Fibrosis in Autosomal Recessive Polycystic Kidney Disease

“…Octreotide and pasireotide, two somatostatin analogs, decrease proliferation of PCK rat CWEC in vitro and inhibit hepatorenal cyst growth in PCK rats in vivo by reducing cAMP levels. Consistently, clinical trials in patients with polycystic liver disease (PLD) and ADPKD showed that octreotide or lanreotide is well tolerated and decreases total liver volume by 4%–6% [13]. …”

“…Accompanying cyst growth and fibrosis, recent reports suggest that inflammation is also present and likely contributes to disease pathogenesis and/or progression [9–12]. Aside from management of symptoms and liver and/or kidney transplant, no effective pharmacologic therapies exist for CHF/ARPKD [13]. …”

Isolated polycystic liver disease and aneurism: a case report

“…disorders are results from structural changes of the biliary tree development and (6) also consist a group of genetic disorders that initiated by mutations in many related genes of PLD and characterized by the development of multiple cholangiocyte derived hepatic cysts that with time replace liver tissue (7,8). Current medical therapies for PLD include symptomatic management (9) and surgical interventions (10).…”

Polycystic Liver Disease: The Benefits of Targeting cAMP

“…3 In cultured cystic cholangiocytes isolated from an animal model of ARPKD, the PCK rat, and from patients with ADPKD, elevated cAMP enhances cell proliferation, accelerates fluid secretion and affects cell cycle progression via its down-stream modulators PKA, EPAC and ERK1/2/MEK. 2, 4, 5 Together, these observations suggest an important role for cAMP machinery in PLD implicating elevated cAMP as a potential therapeutic target.…”

“…Indeed, hepatic cystogenesis has been associated with: (i) enhanced fluid secretion into the cyst lumen; (ii) increased rates of cholangiocyte proliferation; (iii) structural and functional ciliary abnormalities; (iv) abnormal cell-extracellular matrix interactions; (v) impaired cell cycle progression; (vi) morphological centrosomal defects; (vii) global changes in mRNA, microRNA and protein expression; and (viii) increased levels of intracellular cAMP. 2 Experimental evidence suggests that cAMP controls different mechanisms in PLD including cell proliferation and fluid secretion. Indeed, intravenous administration of secretin, a major agonist of cAMP signaling in cholangiocytes via interaction with the basolaterally located secretin receptor, increases fluid secretion in hepatic cysts of ADPKD patients.…”