Overcoming the Dilemma

A safe and effective anti-VEGF aptamer must inhibit pathologic neovasculariza-tion while leaving physiologic neovascularization unaffected. To understand how this was accomplished through the specificity of aptamer binding requires greater familiarity with the VEGF molecule.

VEGF exists as a family of molecules (Kerbel and Folkman, 2002). The molecule referred to in angiogenesis and vascular maintenance is called VEGF-A (for simplicity, the term VEGF will be used in this discussion). Other family members include VEGF-B, whose function is not yet known; VEGF-C and VEGF-D which are involved in lymphangiogenesis; VEGF-E which like VEGF-A, is involved in angiogenesis; and placental growth factor which mediates angio-genesis and inflammation.

In turn, VEGF-A (VEGF) exists as a small group of isoforms, which differ in size and action, but all of which arise from the same VEGF gene (Kerbel and Folk-man, 2002). The gene consists of eight exons and seven introns. During transcription, variable splicing of exons generates VEGF molecules of varying lengths (Kerbel and Folkman, 2002). These isoforms are named for the number of amino acids in the translated protein. The human VEGF isoforms are VEGF121, VEGF145, VEGF165, VEGF189, and VEGF206. The properties of these isoforms vary with their length. With increasing length, VEGF isoforms become more pH basic, more bound to heparin, and less diffusible in tissue.

VEGF isoforms are key to solving the therapeutic dilemma. They are differentially expressed in physiologic and pathologic neovascularization (Kerbel and Folk-man, 2002) providing the potential to selectively inhibit pathologic neovasculari-zation.

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