Clinical Medical Research Award
"A revolution is an idea which has found its bayonets." These words, written by a military and political leader of Genoese ancestry, Napoleon Bonaparte, are exemplified in the work of today's Lasker-Debakey Award recipient, a basic and clinical science leader and another notable Napoleone of Italian ancestry, Napoleone Ferrara. For decades scientists had the idea that there was a diffusible factor that promotes blood vessel growth and in turn that inhibiting this growth might be useful in the treatment of certain diseases. But the identity of this factor proved maddeningly elusive and the concept remained untested. Napoleon Ferrera gave this important idea its bayonets by identifying and characterizing this factor and developing specific antibodies that prevent its function. Ferrara indeed started a therapeutic revolution by showing that inhibition of this molecule's action is highly effective in preventing blindness in people with wet age-related macular degeneration (AMD).
Wet AMD is a devastating and common cause of blindness that affects 1.5 million Americans and countless more world-wide. The disease is uncommon before age 60, but increases rapidly thereafter, affecting nearly 10% of the population over age 80.
Wet AMD arises when blood vessels behind the retina of the eye proliferate abnormally. As proteins leak out of these fragile vessels there is progressive loss of vision that can be both rapid and tragic. At the time of diagnosis patients typically already have significant vision loss, and without treatment within 3 years 75% will deteriorate to blindness, defined as vision worse than 20/200. AMD is particularly devastating because it selectively affects the macula, the center of the visual field; the ability to read is consequently lost early in the course of disease, robbing elderly affected people of one of their remaining connections to the outside world. There was great need for new effective treatment since photodynamic therapy, the previous state-of-the-art treatment, still left 40% of patients with progressive disease and few had any restoration of vision that had already been lost.
The key to improving the treatment of wet AMD proved to be Napoleone Ferrara's identification of a novel protein that elicits blood vessel growth. Every human cell needs a supply of oxygen and nutrients provided via blood vessels; the local blood supply to tissues is dynamic, capable of being remodeled throughout life in response to changing metabolic demands. For example, since the work of Virchow 100 years ago it has been recognized that some cancers make a substance that attracts blood vessels. In the eye, Michaelson proposed in 1948 that a diffusible factor might be responsible for development of both normal and abnormal blood vessel growth, and by 1954 Ashton had demonstrated that increasing oxygen concentrations diminished blood vessel growth in the eye while reduced oxygen levels increased vessel growth.
These observations set the stage for the work of Napoleone Ferrara. Trained as a physician in Italy and specializing in obstetrics, he was deeply interested in reproductive biology and came to the lab of Richard Weiner at the University of California at San Francisco intending to work on reproductive hormones made in the pituitary gland. Here he noted an unusual pituitary cell type that made no hormone but made intimate connections with blood vessels. In an astonishing intuitive leap, Dr. Ferrara guessed that these cells might be making a substance responsible for blood vessel growth. He showed that after growing these cells in culture, the cell-free medium promoted proliferation of endothelial cells, the intrinsic cell of all blood vessels. This provided the basis for a courageous effort to purify and identify this factor using classical biochemical techniques, which Ferrara undertook after becoming a Research Scientist at Genentech. In 1989 he succeeded in this endeavor and showed that this factor was a novel protein that selectively induced proliferation of endothelial cells; he named this factor vascular endothelial growth factor (VEGF). He subsequently isolated the complete VEGF gene and showed that when it was expressed in mammalian cells, VEGF protein was secreted into the medium and promoted endothelial cell proliferation.
An enormous body of work on VEGF has followed, both from Dr. Ferrara's lab and others world-wide. Low oxygen levels in many normal tissues and tumor types led to increased secretion of VEGF. It was shown that VEGF directly binds to a specific receptor on the endothelial cell surface to stimulate proliferation, and this receptor and its signaling pathway was identified and characterized. Finally, genetic ablation of even 1 of the 2 chromosomal copies of VEGF in the mouse was found to be lethal in embryonic development due to failure of normal blood vessel development. These findings collectively documented the essential role of VEGF in the development and dynamic maintenance of a normal blood supply to tissues.
Having the purified VEGF protein enabled Dr. Ferrara to develop highly specific antibodies that selectively bound to VEGF, which he showed blocked its biological activity. This permitted investigation of the utility of these antibodies in the treatment of specific diseases.
One of those diseases was wet AMD. Levels of VEGF were found to be increased in the eyes of patients with wet AMD, potentially accounting for the abnormal blood vessel growth in this disease and suggesting a therapeutic role for anti-VEGF antibodies. Numerous hurdles were overcome in developing the right antibody, formulation and dosage, after which two pivotal phase III clinical trials were begun. One of these was the ANCHOR trial, a two year study of 423 patients with classic wet AMD who were randomized to either photodynamic therapy or intraocular injections of anti-VEGF antibodies. The results were dramatic, obvious, and clinically important. Seemingly miraculously, there were significant improvements in visual acuity in patients receiving anti-VEGF treatment after just one injection; these improvements continued through the first 3 months and were sustained throughout the 2 year trial. In contrast, vision significantly deteriorated in the photodynamic therapy group. After 2 years the anti-VEGF group showed an average gain of about 2 lines on a standard eye chart exam versus a loss of 2 lines in the photodynamic treatment group. This difference is clinically dramatic- at the end of the trial 61% of the patients in the photodynamic treatment group had progressed to blindness, twice the number at the start of the trial. In contrast, only 20% in the anti-VEGF group were blind, which actually represented a decline from the start of the study. These dramatic results led to FDA approval of the use of anti-VEGF antibodies in wet AMD in 2006.
Since that time, there has been extremely rapid adoption of this new treatment, with an estimated 1 million people treated world-wide, attesting to the great unmet medical need and patient recognition of the efficacy of treatment. This constitutes a remarkable advance in the prevention of blindness in the elderly, and also suggests potential future uses of anti-VEGF therapy for other ophthalmologic diseases featuring abnormal blood vessel growth.
The discovery of VEGF by itself was a major scientific advance driven by a desire to understand the basic rules governing blood vessel growth. The development and clinical application of anti-VEGF antibodies to the treatment of wet AMD constitutes a major therapeutic triumph. That Dr. Ferrara not only made the fundamental discovery of VEGF, but also developed the therapeutic anti-VEGF antibodies and was deeply involved in the clinical development program demonstrating their utility in wet AMD constitutes a true tour de force and provides testimony to Dr. Ferrara's intellectual breadth and talent. Napolean Bonaparte also said, "Ability is nothing without opportunity," and special mention should be made of the enabling scientific environment Dr. Ferrara found when he started this work at Genentech as well as this company's support for Dr. Ferrara's early basic studies at a time when there was little expectation of therapeutic payoff. Dr. Ferrara's success in the prevention of blindness in wet AMD with anti-VEGF antibodies is a spectacular achievement and serves as a potent reminder of the crucial links between outstanding basic science and disease-transforming therapeutics. From this Napoleone's work comes hope and expectation that we will see many more great scientific ideas turned into therapeutic bayonets.