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不知道你对这技术为什么兴趣。。。和HBV无关
这是ECCO摘要的原文。27日会有Presentation
Abstract title:
HIF-2 alpha targeting with a novel RNAi delivery platform as therapy for renal cell carcinoma
S. Wong(1), W. Cheng(1), D. Wakefield(2), A. Almeida(2), A. Blokhin(2), L. Almeida(2), H. Hamilton(1), V. Subbotin(3), J. Hegge(1), S. Bertin(1), T. Milarch(4), R. Schmidt(4), Z. Neal(1), A. Perillo-Nicholas(2), G. Zhang(1), J. Montez(1), A. Andersen(1), D. Rozema(1), D. Lewis(5), S. Kanner(1)
(1)Arrowhead Research Corporation, Biology, Madison, USA
(2)Arrowhead Research Corporation, Chemistry, Madison, USA
(3)Arrowhead Research Corporation, Pathology, Madison, USA
(4)Arrowhead Research Corporation, LAR, Madison, USA
(5)Arrowhead Research Corporation, Corporate, Madison, USA
Background: Therapies for metastatic clear cell renal cell carcinoma (ccRCC) including agents that target the VEGF/VEGFR or mTor signaling pathways have become the standard-of-care and have improved patient outcomes, but emergence of resistance to these agents is common. Novel therapies targeting parallel or orthogonal pathways are needed for patients with resistant tumors. Over 90% of ccRCC tumors express a mutant form of the Von Hippel-Landau protein (pVHL), an E3 ubiquitin ligase. The mutant pVHL is unable to polyubiquitinate the transcription factor hypoxia-inducible factor 2a (HIF-2a), leading to its accumulation during tumor hypoxia and promoting its activity as a tumorigenic driver. We have developed an RNAi-based approach for inhibiting HIF-2a expression using a targeted platform called Dynamic Polyconjugate (DPC), which enables efficient delivery of siRNA targeting HIF-2a directly to ccRCC tumors.
Materials and Methods: The DPC platform comprises a membrane active polymer to promote RNAi trigger endosomal release, a ligand that binds to alphaV-containing integrins on tumor cells, reversible masking to prevent polymer activity prior to endosomal compartmentalization, and an RNAi trigger to HIF-2a.
Results: Target validation was achieved by expression of an inducible shRNA to HIF-2a in established ccRCC tumors in mice, resulting in significant HIF-2a gene knockdown and tumor regression after induction. The integrin-targeting DPC (ITG-DPC) exhibits significant internalization in multiple renal tumor cell lines both in vitro and in tumor bearing mice. Treatment of nude mice harboring established orthotopic A498 ccRCC tumors with weekly injections of ITG-DPC led to >80% knockdown of HIF-2a mRNA in tumors. Furthermore, tumors from ITG-DPC treated mice exhibited statistically significant reductions in size and weight, massive apoptosis of tumor cells, reduction in the tumor-expressed VEGF-A biomarker and ablation of neovascularization as evaluated by CD31 staining.
Conclusion: These data indicate that ccRCC targeting by delivery of a potent and specific RNAi trigger to HIF-2a has the potential to significantly impact late stage ccRCC progression.
Conflict of interest: Ownership: We are employees and stockholders of Arrowhead Research Corporation.
Keywords:
HIF-2 alpha
RNAi
integrin |
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发表于 2015-9-17 06:39
