Morpholino, also known as morpholino, is a molecule used to modify gene expression. In molecular biology, morpholino groups may be found in molecules other than oligonucleotides. The term “morpholino” refers to its oligonucleotide form, the phosphorodiamidate morpholino oligomers (PMO). Morpholino groups are synthetic molecules obtained by redesigning the structure of natural nucleotides. They are mostly 25 bases in length and are complementarily bound to RNA in a standard nucleotide base-pairing manner. Structurally, morpholino bases differ from DNA in that although the former has standard nucleotide bases, these bases are attached to the morpholine ring rather than the deoxyribose ring. Morpholino can act by occupying sites where mRNA acts with other molecules in vivo.
Recently, Balamurali K. Ambati et al. from the University of Utah found that morpholine bases elevate the expression of soluble vascular endothelial growth factor receptor-1 (Flt-1) and as a result reduce angiogenesis in the eye and in tumors. The results were published in the March 15 issue of Public Library of Science – General (PLoS One).
The pathogenesis of several common visual problems and cancers involves neovascularization. Soluble Flt-1 (sFlt-1) is known to be expressed by selective splicing of the Flt-1 gene, which retains the Flt-1 ligand-binding region during splicing, but lacks the transmembrane structural domain and intracellular kinase structural domain of the Flt-1 protein. Therefore, sFlt-1 becomes an endogenous inhibitor of vascular endothelial growth factor A (VEGF-A) regulation of angiogenesis. It was found that synthetic morpholine-based oligomers could regulate the expression diversity of selective splicing of Flt-1. For this reason, the researchers envisioned that morpholine-induced upregulation of sFlt-1 might inhibit neovascularization.
Experimental results showed that morpholinyl oligomers could purposefully act on Flt-1 mRNA exons and endon 13 junctions to promote the expression of more soluble receptors than membrane-coupled receptors. It was found that the amount of damaged tissue was effectively reduced in gene copy number variation (CNV) induced by laser as well as in breast cancer. Thus, morpholino-induced upregulation of sFlt-1 did inhibit neovascularization. This provides a new idea for the treatment of malignant angiogenic diseases. (BioValeBioon.com)
doi: 10.1371/journal.pone.0033576
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Morpholino-Mediated Increase in Soluble Flt-1 Expression Results in Decreased Ocular and Tumor Neovascularization
Leah A. Owen, Hironori Uehara, Judd Cahoon, Wei Huang, Jacquelyn Simonis, Balamurali K. Ambati.
Angiogenesis is a key process in several ocular disorders and cancers. Soluble Flt-1 is an alternatively spliced form of the Flt-1 gene that retains the Soluble Flt-1 is an alternatively spliced form of the Flt-1 gene that retains the ligand-binding domain, but lacks the membrane-spanning and intracellular kinase domains of the full-length membrane bound Flt-1 (mbFlt-1) protein. Thus, sFlt-1 is an endogenous inhibitor of VEGF-A mediated angiogenesis. Synthetic morpholino oligomers directed against splice site targets can We hypothesize that morpholino-induced upregulation of sFlt-1 will suppress angiogenesis in clinically relevant models of macular degeneration and breast cancer.Morpholino oligomers targeting the VEGFR1 mRNA exon/intron 13 junction promote production Morpholino oligomers targeting the VEGFR1 mRNA exon/intron 13 junction promote production of soluble FLT-1 over membrane bound FLT-1, resulting in suppression of lesional volume in laser induced CNV and breast adenocarcinoma. Thus, Thus, morpholino manipulation of alternative splicing offers translational potential for therapy of angiogenic disorders.
