Ventures in Translation features innovators in the field of vitreoretinal disease. Successful translation of scientific ideas to useful medical treatments and technologies requires many elements. Each of the innovators featured here has a story to tell that often combines an exceptional understanding of disease, foresight, perseverance, and an ability to obtain funding for an unrecognized technology. The stories featured here will provide a snapshot of what it has taken to bring these breakthroughs to our patients. The authors range from scientists to clinicians to bankers to venture capitalists, and some will be a little of all.

In this installment, Robert D'Amato, MD, of Children's Hospital Boston, describes his discovery of the anti-angiogenic properties of thalidomide, a drug that had previously been mostly abandoned for medical use because of devastating side effects. His research resulted in new applications for an existing drug for cancer treatment and, although it did not prove to be successful in treating age-related macular degeneration as was hoped, the experience provides important lessons regarding medical research and development. -Elias Reichel, MD

BRIEF HISTORY
Thalidomide is a compound derived from glutamic acid. It was developed in the 1950s by Chemie Gruenthal (Stolberg, Germany) in a search to find antibiotics that could be manufactured at a relatively low cost from peptides.1 From these efforts, thalidomide was determined to demonstrate no antibiotic activity; however, it produced sedative and anti-anxiety effects in humans on observation and had minimal teratogenic effects on rodents in the laboratory.2

Initially, thalidomide was primarily used for psychiatric patients as an alternative for valium. The drug was first released in 1957 as an over-the-counter sedative medication sold under the brand name Contergan. After the drug was discovered to have anti-nausea effects, it was used in several countries in Europe and South America, as well as in Australia and Canada for the treatment of morning sickness associated with pregnancy.

Its use was delayed in the United States, however, because Frances Kelsey, MD, PhD, of the US Food and Drug Administration (FDA), required US distributor Richardson-Merrell (Kansas City, MO), to provide more toxicology data prior to the drug's approval. In the time that it took the company to compile these data, infants with severe limb deformities were being born to women in the countries where thalidomide was being used.1 Stunted limbs (some as severe as phocomelia) and other deformities were seen in affected infants.

THE SEARCH FOR AN ANGIOGENESIS INHIBITOR
In the early 1990s, I began a search for drugs already in existence that might have antiangiogenic effects or antiblood–vessel properties. I went about this task by creating a list of side effects I would expect a person to have if they took a drug that was a blood-vessel inhibitor. At first, I considered my own body; a delay in wound healing seemed the most likely side effect. For example, if I cut my finger, it would take longer to heal if I were taking an antiangiogenic drug. After a search for drugs that had been described to delay wound healing, I failed to find many aside from steroids and chemotherapy drugs.

It then occurred to me, however, that I was considering this effect from only my own point of view; however, an antiangiogenic effect would cause amenorrhea, a halt to menstrual cycles, in a woman. Subsequently, I performed a search of all the drugs known to induce amenorrhea and found there were many. In trying to narrow the list, I searched drugs that might also cause blood vessel growth to stop in pregnancy, causing a birth defect. This list was also rather large. When I crossed these two lists, however, only five compounds remained that were shown to cause both amenorrhea and birth defects. The most interesting on that list was thalidomide because no cause had ever been found to explain this effect.

THALIDOMIDE EMERGES AS CANCER DRUG
We then tested thalidomide extensively in the laboratory setting using rabbit models of corneal neovascularization. Upon administration of oral thalidomide to the rabbits, we showed that blood vessels stopped growing, as compared with controls, where they did not.3 This was the first study to show that thalidomide was an angiogenesis inhibitor.

Subsequently, we transplanted tumors onto the backs of rabbits. Treatment with thalidomide slowed the tumor growth, providing proof that antiangiogenic therapy with thalidomide could be applied to cancer treatment,4 a theory which was first proposed by M. Judah Folkman, MD, in 1971.5 Based on these findings, clinical trials were begun to test the efficacy of thalidomide for cancer treatment. As a result of these clinical trials, thalidomide is now FDA- approved for the treatment of multiple myeloma.

THALIDOMIDE FAILS FOR AMD
Clinical trials for thalidomide to treat age-related macular degeneration (AMD) were begun in the mid-1990s. The dose that one would need systemically to achieve blood vessel inhibition in the eye was similar to what we were using in the cancer trials. The sedative properties of the drug, however, proved to be an issue for older patients. Patients in the cancer trials tended to be younger and more tolerant of this side effect, but the older AMD patients had a more difficult time recovering from the sedation; many patients dropped out due to intolerance. Thus, thalidomide never made it further than phase 1 trials for AMD.

LESSONS LEARNED FOR OPHTHALMOLOGY
The main lesson that was reinforced by the thalidomide experience was that drugs that work in one patient population are often unsuitable for a different group of patients. Because angiogenesis is a common factor in both cancer and AMD, it would stand to reason that many drugs for cancer may be applicable to therapy for AMD. Although this is true in some cases, the tolerance level of a patient with a life-threatening disease is far greater than that of a patient with AMD. This was also seen when interferon alpha-2a was investigated as a therapy for AMD.6 Higher doses were not tolerated well. Another lesson learned from the thalidomide experience is that for the eye, local delivery of drug appears to offer the most benefit with the least side effects.The burden is heavier when trying to apply systemic drugs to the eye for AMD. The experience of thalidomide reminds us that there may be multiple applications for existing drugs, even for those toxic in certain patient populations, if the side effect profiles are carefully examined.

Robert D'Amato, MD, PhD, is Chair in Surgical Research and Director of the Center for Macular Degeneration Research at Children's Hospital Boston and is an Associate Professor of Ophthalmology at Harvard Medical School. He reports that he has no financial interests to disclose in relation to the content of this article. Dr. D'Amato can be reached at +1 617 919 2247; fax: +1 617 730 0231.

Elias Reichel, MD, is Vice Chair for Research and Education, Department of Ophthalmology, at the New England Eye Center, Tufts University School of Medicine in Boston. He is a member of the Retina Today Editorial Board and may be reached at EReichel@tufts-nemc.org.

Editor-in-Chief Rachel Renshaw provided editorial assistance for this article.

  1. Silverman WA. The schizophrenic career of a "monster drug" [Commentary]. Pediatrics. 2002;110(2):404–406.
  2. Cahaen R, Sautai M, Montagne J. Research on the teratogenic effect of 2-diethylaminopropiophenone [article in French]. Med Exp Int J Exp Med. 1964;10:201–224.
  3. D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Prac Natl Acad Sci U S A. 1994;91:4082–4085.
  4. Verhaul HMW, Panigraphy D, Yuan J, D'Amato RJ. Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumor growth in rabbits. Brit J Cancer. 1999;79(1):114–118.
  5. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21)1182–1186.
  6. Fung WE. Interferon alpha 2a for treatment of age-related macular degeneration. Am J Ophthalmol. 1991;112(3):349–350.