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Therapeutic siRNA targeting endothelial KDR decreases portosystemic collateralization in portal hypertension.

ABSTRACT: Development of portosystemic collateral vessels and gastroesophageal varices is responsible for the most serious clinical consequences of portal hypertension, but effective clinical therapies are limited. Here we developed and investigated the therapeutic potential of an innovative liposomally-formulated short-interfering RNA (siRNA) technology based on clinical stage components, capable to attenuate production of the endothelial kinase insert domain receptor (KDR), which controls portosystemic collateralization and contributes to disease progression and aggravation. These siRNAs were first validated in vitro, and then, their therapeutic potential on portosystemic collateralization and pathological angiogenesis was tested in vivo in mouse models of portal hypertension (portal vein-ligation). siRNAKDR-lipoplexes efficiently transported siRNAKDR to vascular endothelial cells in mesenteric microvenules and portal vein of portal hypertensive mice, where collaterogenesis and angiogenesis take place. This systemic treatment significantly downregulated pathological KDR overexpression, without causing complete KDR knockout, preserving homeostatic baseline KDR levels and thus limiting adverse effects. siRNAKDR-lipoplex-induced endothelial-specific KDR knockdown drastically reduced by 73% the portosystemic collateralization, and impaired the pathologic angiogenic potential of vascular endothelial cells at different levels (cell proliferation, sprouting and remodeling). Targeting endothelial KDR with therapeutic siRNAKDR-lipoplexes could be a promising and plausible treatment modality for attenuating the formation of portosystemic collaterals in a clinical setting.

SUBMITTER: Gallego J

PROVIDER: S-EPMC5665956 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and aimsTransjugular intrahepatic portosystemic shunt (TIPS) is used for decompressing clinically significant portal hypertension. The aims of this study were to evaluate clinical outcomes and adverse events associated with this procedure.MethodsRetrospective single-center study including 78 patients submitted to TIPS placement between January 2015 and November 2018. Follow-up data were missing in 27 patients, and finally 51 patients were included in the study sample. Data collected from individual registries included demographics, comorbidities, laboratory results, complications, and clinical results according to the indication.ResultsAverage pre-TIPS portosystemic pressure gradient decreased from 18.1 ± 5 to 6 ± 3 mm Hg after TIPS placement. Indications for TIPS were refractory ascites (63%, n = 49), recurrent or uncontrolled variceal bleeding (36%, n = 28), and Budd-Chiari syndrome (1.3%, n = 1). TIPS-related adverse events occurred in 29/51 (56.8%) patients, with hepatic encephalopathy (HE) in 21 (41%) patients, sepsis in 3, liver failure in 2, hemolytic anemia in 1, acute pulmonary edema in 1, and capsular perforation in 1 patient. Mean follow-up was 15.7 ± 15 months. First-month mortality was 11.7% (n = 6) (sepsis, n = 3; acute liver failure, n = 2; and recurrence of variceal bleeding, n = 1) and was significantly higher for patients with Child-Pugh >9 points (p = 0.01), model of end-stage liver disease (MELD) scores >19 (p = 0.02), and for patients with a history of HE before the procedure (p = 0.001). Older age (p = 0.006) and higher levels of creatinine (p = 0.008) were significantly higher in patients developing HE after TIPS. Ascites persisted in 21.2% (7/33 patients) and was more frequent in patients with lower baseline albumin levels (p = 0.003). Recurrent variceal bleeding occurred in 22% (n = 4/18 patients) and was more frequent in patients with lower baseline hemoglobin levels (p = 0.03).ConclusionTIPS is effective in up to 80% of patients presenting with variceal bleeding or refractory ascites. Careful patient selection based on age and HE history may reduce adverse events after TIPS.

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Therapeutic siRNA targeting endothelial KDR decreases portosystemic collateralization in portal hypertension.

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