Targeted siRNA Therapeutics: Big Potential from Small RNAs in Liver Disease. Published in Scientific Reports 2017

Published in Scientific Reports 2017. “Therapeutic siRNA targeting endothelial KDR decreases portosystemic collateralization in portal hypertension”, by Javier Gallego*, Ester Garcia-Pras*, Marc Mejias, Nuria Pell, Ute Schaeper and Mercedes Fernandez (*co-first authors). Corresponding author: Mercedes Fernandez. Scientific Reports 2017;7:14791.

Published in Abstract form in Hepatology 2017: “Gene therapy with endothelial-specific liposomal short interfering siRNA targeting kinase insert domain receptor inhibits portosystemic collateralization in portal hypertension”, by Gallego J, Garcia-Pras E, Mejias M, Pell N, Schaeper U, Fernandez M. Hepatology 66(1) (Suppl): 141A (2017).

Presented in a Parallel Session at the 68th Annual Meeting of the American Association for the Study of Liver Disease (AASLD) (Washington DC, October 23, 2017). The speaker, Nuria Pell, earned the AASLD Basic Science Young Investigator Travel Award, which recognizes outstanding young basic science researchers working on liver disease.

What is new about this study? This study describes an innovative therapeutic strategy for treatment of one of the most clinically relevant complications of chronic liver disease, the formation of portosystemic collateral vessels and gastroesophageal varices. This treatment is based on the short interfering RNA (siRNA) technology, which has emerged as one of the most promising platforms for therapeutic product development. In particular, in collaboration with Silence Therapeutics, we have developed a novel and effective siRNA delivery system (siRNAKDR-lipoplexes), based on clinical stage components, to efficiently and specifically target the kinase insert domain receptor KDR in vascular endothelial cells in vivo after systemic intravenous administration. The KDR receptor plays a key role in portosystemic collateralization and contributes to disease progression and aggravation, as we have previously shown, making it an attractive therapeutic target.

What is the key finding? Our results demonstrate that therapy with siRNAKDR-lipoplexes markedly ameliorates the development of portosystemic collateral vessels and impairs the pathological angiogenic potential of endothelial cells in a murine model of portal hypertension (a syndrome that occurs in chronic liver disease). Our findings also demonstrate that the mechanisms underlying the decrease in collateralization after KDR knockdown include reduced endothelial cell proliferation and decreased angiogenesis and vascular remodeling.

Which could hopefully be the future impact of this work? This treatment could be a promising and plausible therapeutic modality for attenuating the formation of portosystemic collateral vessels in a clinical setting. Of note, this therapeutic intervention may potentially prevent the formation of large varices from small varices. This is important because new collaterals and varices develop each year during the evolution of chronic liver disease, and, currently, no treatment can prevent this development. Of interest, a related type of formulation developed by Silence Therapeutics has been shown to be clinically acceptable for systemic administration of siRNAs and is currently successfully tested in several clinical trials in patients with advanced solid tumors, further supporting the translational relevance and therapeutic potential of this approach for chronic liver disease in a clinical context. Given the emerging roles of angiogenesis in a number of human pathologies, including inflammation, obesity and tumor growth, siRNAKDR-lipoplexes may also provide a novel strategy to treat a wide spectrum of diseases.

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