Journal of Genetic Syndromes & Gene Therapy
Open Access
ISSN: ISSN: 2157-7412
ISSN: ISSN: 2157-7412
Vincent H. Gattone II and Robert L. Bacallao
Autosomal dominant (AD) polycystic kidney disease (PKD) is a major cause of end-stage renal disease, with neither a cure, nor an approved treatment to slow its progression. In the past decade significant advances have been made in understanding the cellular signaling pathways disrupted in PKD. Understanding the changes in signaling pathways linked to mutations in PKD1 and PKD2 as well as other renal cystic genes led to preclinical trials and Phase II & III human trials to ameliorate PKD progression. Since PKD is a proliferative disease, some treatments are aimed at neoplastic cell proliferation (i.e. src and MAPK inhibition). PKD is also associated with decreased cellular calcium and increased cAMP, so other treatments targeted cellular Ca (i.e. calcimimetics and polycystin 2 agonists)
or G-protein linked receptors (i.e. the vasopressin V2 receptor and somatostatin receptor inhibitors). Fluid secretion through the cystic fibrosis transmembrane conductance regulator (CFTR, a chloride channel) also contributes to disease progression and therapies blocking chloride secretion are also possible therapeutic agents. Significantly, the renin- angiotensin system is responsible, at least in part, for PKD associated hypertension, and drugs targeting this pathway are also being evaluated as therapies for ADPKD progression. Assessment of efficacy in humans with ADPKD is complicated by the slow progressive nature of the disease, but the CRISP imaging studies have provided important data on renal cystic enlargement over time. Based on numerous preclinical studies in rodent models, several human clinical trials are currently being performed, suggesting that a treatment to inhibit progression of
ADPKD and other renal cystic conditions may be available in the near future.