Modulation of eIF5A expression using SNS01 nanoparticles inhibits NF-κB activity and tumor growth in murine models of multiple myeloma.

Molecular Therapy : the Journal of the American Society of Gene Therapy
Catherine TaylorJohn Thompson

Abstract

Despite recent advances in the first-line treatment of multiple myeloma, almost all patients eventually experience relapse with drug-resistant disease. New therapeutic modalities are needed, and to this end, SNS01, a therapeutic nanoparticle, is being investigated for treatment of multiple myeloma. The antitumoral activity of SNS01 is based upon modulation of eukaryotic translation initiation factor 5A (eIF5A), a highly conserved protein that is involved in many cellular processes including proliferation, apoptosis, differentiation and inflammation. eIF5A is regulated by post-translational hypusine modification, and overexpression of hypusination-resistant mutants of eIF5A induces apoptosis in many types of cancer cells. SNS01 is a polyethylenimine (PEI)-based nanoparticle that contains both a B-cell-specific expression plasmid expressing a non-hypusinable mutant of eIF5A and a small interfering RNA (siRNA) which depletes endogenous hypusinated eIF5A. Reducing hypusine-modified eIF5A levels was found to inhibit phosphorylation and activity of ERK MAPK and nuclear factor-κB (NF-κB), and thus sensitize myeloma cells to apoptosis resulting from transfection of a plasmid expressing eIF5A(K50R). SNS01 exhibited significant antitumor...Continue Reading

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Feb 27, 2014·Molecular Therapy : the Journal of the American Society of Gene Therapy·Sarah M FrancisJohn E Thompson
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