8. Guanylyl Cyclase A-Targeted Gene Therapy Ameliorates Disease Progression in Autosomal Recessive Polycystic Kidney Disease
Authors: Sara J. Holditch, Alessandro Cataliotti, Vicente Torres, Yasuhiro Ikeda
Journal: Molecular Therapy (2015)

Although Polycystic Kidney Disease (PKD) is a leading cause of renal and hepatic pathologies, there are limited therapies available. PKD presents with cystic manifestations leading to organ enlargement, loss of functional parenchyma, progressive organ dysfunction and hypertension, ultimately leading to organ failure. Cardiac B-type natriuretic peptide (BNP) is central in the control of intravascular volume by regulating water and sodium homeostasis. Additionally, BNP has been characterized to counteract several key properties contributing to cystic disease progression such as; inhibiting fibroblast proliferation, preventing monocyte chemotaxis, antagonizing vasopressin (AVP)-mediated water reabsorption, and preventing renin-angiotensin-aldosterone activation. Along with its blood pressure-lowering propensity, BNP presents a promising therapeutic strategy in hindering the progression of PKD. We investigated the therapeutic effect of vector mediated BNP expression in the rat model of ARPKD (PCK). Littermate PCK neonates received placebo, or single intraperitoneal injection of adeno-associated virus 9 (AAV9) vectors at 1.0E+12 genome copies/kg, under the control of an internal CMV promoter. Three months post treatment, kidney weight was significantly reduced (TKW/BW 12.6±1.7* vs 14.5±2.0) in treated PCK, along with a significant reduction in renal cyst burden. Blood and urine analysis confirmed decreased disease with BNP treatment, with a nearly 50% reduction in 24 hour urine output, (8.8±3* vs 13.2±1 mL/24-hr), higher creatinine clearance (eGFR: 0.51±0.1* vs 0.26±0.2 mL/min), decreased proteinuria (490±270* vs 270±190 mg/dL), and increased urine concentrations of sodium (130±39* vs 85±20 mmol/L) and potassium (395.8±41* vs 282.1±75 mmol/L) in treated PCK, compared to controls, respectively. Excretion of renal injury markers, kidney injury molecule-1 and lipocalin-2, was lower in BNP-treated rats compared to controls. BNP treatment also preserved glomerular architecture, retarded basement membrane thickening and glomerular sclerosis in PCK. Real-time RT-PCR analysis demonstrated that BNP treatment significantly reduced renal and hepatic expression of the fibrosis-associated genes; Collagen, fibronectin, and transforming growth factor β. Furthermore, liver protection, in BNP-treated PCK, was observed through decreased expression of fibrosis marker desmin, and galectin-3, along with decreased cyst-index. Additionally, echocardiography demonstrated preserved cardiac function with treatment (ejection fraction: 78±5 * vs 73±5%) at three months, though both groups remained normotensive. Together, these observations indicate that a single intraperitoneal AAV9 injection elicits therapeutic benefit in protecting against declining hepatic and renal function, remodeling of healthy parenchyma, and increased cyst burden, while providing cardiac protection. The present study further suggests that sustained GC-A activation provides a novel opportunity for the treatment of polycystic kidney and liver diseases.±±