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Vascular Endothelial Growth Factor and Age-Related Macular Degeneration: from Basic Science to Therapy

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Vascular Endothelial Growth Factor and Age-Related Macular Degeneration: from Basic Science to Therapy LASKER~DEBAKEY CLINICAL MEDICAL RESEARCH AWARD COMMENTARY Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapy Napoleone Ferrara It is almost intuitive that blood vessels have a mediators of angiogenesis, a major technologi- lular protein, because of its lack of secretory central role in biology and medicine. Indeed, cal challenge in those days. signal peptide8. This finding caused several even though the concept of blood circula- investigators to doubt that a protein with such tion was not established until a few centuries From neuroendocrinology to angiogenesis characteristics could regulate angiogenesis, a ago, mankind had known for millennia that and vascular endothelial growth factor process that requires diffusion in the environ- blood vessels are indispensable for bringing I studied Medicine at the University of Catania ment and generation of gradients. I speculated nourishment to organs and limbs. The con- Medical School, in the homonymous southern that the endothelial cell mitogenic activity in verse notion—that growth of blood vessels can Italian city. It was a fortunate circumstance the follicular cell–conditioned medium may promote or facilitate disease—is much more that Umberto Scapagnini had recently joined be due to a secreted protein. I then pursued the recent. Starting in the mid-nineteenth cen- our medical school as chairman of pharmacol- isolation of this molecule, hoping that it would tury, several investigators, including Rudolf ogy. Attending his lectures planted the seed for prove to be a key player in angiogenesis. Virchow, noted that tumor growth is frequently my future career. Scapagnini had made impor- In 1988, I joined Genentech as a research sci- accompanied by increased vascularity1. Major tant contributions to neuroendocrinology entist. Given my background in endocrinology, conceptual advances took place in the 1930s after spending several years at the University I participated in the development of relaxin, a and 1940s, when it was hypothesized that the of California–San Francisco (UCSF) in the lab hormone thought to facilitate parturition. The ability to induce new vessel growth through of William Ganong, one of the pioneers in this company has a policy of allowing some time release of vasoproliferative factors confers a field. While still a medical student, I joined for discretionary research, and I took advan- growth advantage on tumor cells2,3. Scapagnini’s group. Wishing to pursue research tage of this opportunity to work on my favorite At about the same time, seminal obser- in the same field, in 1983 I began a postdoctoral project. I was fortunate to find at Genentech vations implicating blood-vessel growth in fellowship in Richard Weiner’s laboratory in the not only state-of-the-art technology but also intraocular disorders leading to blindness Reproductive Endocrinology Center at UCSF. great colleagues and collaborators, including were made. In 1948, Isaac Michaelson pro- While culturing different cell types from Bill Henzel, David Leung and Dave Goeddel. In posed, on the basis of his elegant embryologic bovine pituitary, I stumbled on a population 1989, we obtained the amino-terminal amino and clinicopathological studies, that a diffus- of non–hormone-secreting cells with unusual acid sequence of the purified endothelial mito- ible factor (named afterward ‘factor X’) could characteristics6. We identified these cells as gen and found that it did not match any known be responsible not only for the development follicular cells. The function of follicular cells sequence in available databases. Because this of the normal retinal vasculature but also for was poorly understood, but their cytoplasmic protein had selective growth-promoting effects pathological neovascularization in proliferative projections establish intimate contacts with on vascular endothelial cells, I proposed the diabetic retinopathy and other disorders4. perivascular spaces, a finding that led some term ‘vascular endothelial growth factor’ Later on, Judah Folkman’s hypothesis that early investigators to suggest that these cells (VEGF)9. We then isolated bovine and human antiangiogenesis could be a strategy to treat have a role in regulating growth or mainte- cDNA clones encoding VEGF10. We identified cancer and possibly other disorders5 generated nance of the pituitary vasculature. I was so three different human clones encoding mature a great deal of enthusiasm and gave a major intrigued by this possibility that I tested fol- proteins of 121, 165 and 189 amino acids, 10 boost to the field. However, harnessing such licular cell–conditioned medium on cultured respectively (VEGF121, VEGF165, VEGF189) . therapeutic potential first required the iso- endothelial cells. To my delight, the medium Importantly, a typical secretory signal sequence lation, sequencing and cDNA cloning of the strongly promoted endothelial cell growth7. preceded the amino terminus, confirming that At that time, basic fibroblast growth factor VEGF is a secreted protein. (bFGF) was thought to be the major endothe- After our cloning paper was accepted for Napoleone Ferrara is at Genentech, South San lial cell mitogen and angiogenic factor in publication10, we learned, to our surprise, Francisco, California, USA. pituitary and other organs. However, in 1986 that a group at Monsanto Company led by e-mail: [email protected] it became known that bFGF is an intracel- Daniel Connolly had submitted at about the natURE MEDICINE VOLUME 16 | NUMBER 10 | OCTOBER 2010 xix commentary Fab 2, in spite of its lower binding affinity for factor X, including diffusibility and hypoxia VEGF, is the main signaling receptor, whereas inducibility28. So several groups converged on VEGFR-1 has highly complex and context- this molecule as a potential mediator of retinal VEGF dimer dependent roles18. ischemia-related neovascularization. In 1994, To elucidate the role of VEGF in vivo, we in a collaborative study with Lloyd Aiello and developed a series of pharmacological and George King at the Joslin Diabetes Center in genetic tools to inhibit its function. In 1993, Boston, we found a striking correlation between Fab we reported that administration of a VEGF- VEGF concentrations, measured in the eye flu- specific monoclonal antibody substantially ids from 164 patients, and active proliferative reduced growth of several human tumor cell retinopathy associated with diabetes, occlusion lines implanted in immunodeficient mice19. of central retinal vein or prematurity29. Tony These studies resulted in the clinical develop- Adamis and colleagues at Massachusetts Eye Figure 1 Structure of the VEGF-ranibizumab ment of a humanized variant of this VEGF- and Ear Infirmary in Boston also reported complex, showing two Fab molecules binding 20 the symmetrical poles of the VEGR dimer40. specific antibody (bevacizumab), which has elevated VEGF amounts in the vitreous of indi- 30 Compared to the bevacizumab Fab, ranibizumab been approved for therapy of multiple tumor viduals with diabetic retinopathy . has five residue changes in the variable domains types21. Meanwhile, it became known that VEGF and one in the constant region. Structural and functional studies of upregulation in the eye is not limited to VEGFR-1 led to the discovery that, of the seven is chemic retinal disorders. The localization of extracellular immunoglobulin-like domains, VEGF in choroidal neovascular membranes same time a manuscript reporting the cloning domain 2 is the crucial element for high-affinity from individuals with neovascular (wet) age- of vascular permeability factor (VPF)11. These VEGF binding22. This finding enabled the related macular degeneration (AMD)—the investigators described a human clone that design of chimeric soluble receptors (known leading cause of irreversible severe vision loss in encoded a protein identical to one of the iso- also as ‘VEGF traps’) as potent inhibitors that, the older adult population—was reported31,32. forms that we identified—VEGF189. Connolly unlike many monoclonal antibodies, can Choroidal neovascularization (CNV), which and colleagues had followed up on the elegant block VEGF across species. The availability of results in vision-impairing exudation and early work by Harold Dvorak at Beth Israel these tools allowed us to establish the role of hemorrhage, is a prominent feature of wet Hospital in Boston, who identified VPF as a VEGF in angiogenesis associated with some AMD and affects the macula, a photoreceptor- protein that increases vascular permeability crucial physiological processes such as organ dense area in the central portion of the retina in the skin12. However, because VPF had not and skeletal growth23,24 and differentiation of that is responsible for central, high-resolution been purified to homogeneity and sequenced, the ovarian corpus luteum25. Inactivation of vision33. its identity remained unknown12. the Veg fa gene in mice provided evidence for Proof-of-concept studies supported the indispensable role of this molecule in the the hypothesis that VEGF is a major Establishing the role of VEGF in development of the vasculature and revealed player in intraocular neovascularization. angiogenesis that loss of even a single Veg fa allele results in Administration of chimeric soluble VEGF The cloning of VEGF (known also as VEGF-A early embryonic lethality26,27. receptors markedly reduced retinal neo- following the discovery of several family vascularization in a mouse model of retin- members—VEGF-B, VEGF-C, VEGF-D and VEGF
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