Stephen F. Austin State University
Written February, 2002
In a society where technology has lengthened the average lifespan, age-related disorders present new treatment challenges. In the United States, senior citizens over the age of 65 account for 21% of the population (US, 2001). This group of people will experience changes in their perceptual systems as they age, making it harder for them to function. Some of these changes will occur systematically and naturally, while others will result from disease. In the case of vision, age-related macular degeneration (AMD) is the leading cause of visual impairment in the elderly population (Levin, 1997). Experts estimate that ten million senior citizens over the age of 75 suffer with AMD, approximately one third of Americans 75 and older (Levy, 1999).
AMD attacks the retina of aging eyes and is found in two forms. The most common form diagnosed is dry-type AMD. In this disease, accounting for 85% of all AMD diagnoses (Thompson & Daniels, 1998), the layers of the retina deteriorate and thin in the fovea resulting in severe vision loss in the central line of vision. Often, fat deposits, called drucen, develop and further impair vision. Wet-type AMD makes up the remaining 15% of AMD diagnoses and progresses more rapidly and painfully than dry-type AMD. This form of AMD is responsible for severe visual impairment in 90% of all AMD cases diagnosed (Gisele & Bressler, 2001; Thompson & Daniels, 1998). Although dry-type AMD does not usually predict wet-type AMD, between 10-20% of patients with dry-type AMD eventually develop wet-type AMD (Gisele & Bressler, 2001).
Wet-type AMD is characterized by choroidal neovascularization (CNV), or the growth of new blood vessels in the layers of the retina (Gisele & Bressler, 2001). Not only do these new capillaries impede vision by blocking incoming light, they also leak blood into the surrounding tissues causing further damage. Currently, the Federal Drug Administration (FDA) has only approved two treatment techniques for wet-type AMD (Yam & Netting, 1999; Visudyne, 2000). Researchers first developed photocoagulation, a procedure utilizing lasers to cauterize new capillaries and seal leaks. Unfortunately, this treatment is only useful in approximately 10% of patients who seek it and, while photocoagulation does decrease vision loss, the results are only short-term and the risk of damage to nearby photoreceptors is high (Gisele & Bressler, 2001; Yam & Netting, 2001; Thompson & Daniels, 1998). The most recently approved treatment option is verteporfin photodynamic therapy, a two-step treatment approved by the FDA in 2000 (Visudyne, 2000). Verteporfin is a light-activated drug that is first injected and then activated by thermal light to reduce new capillaries (Gisele & Bressler, 2001). Treatments not yet approved for commercial use include radiation therapy, surgical therapies, and pharmaceutical therapies (Thompson & Daniels, 1998).
The ideal tool against AMD is prevention, but the ideal treatment of the future may be a drug therapy. Ophthalmologic research on AMD has been very active in recent years, producing much more information than ever before (Guttman, 2001). Pharmaceutical research for the treatment of wet-type AMD focuses primarily on antiangiogenic drugs, which would inhibit and sometimes reverse the effects of CNV. Results of clinical studies, however, show mixed results and some scientists do not see potential in the ongoing research (Gisele & Bressler, 2001). Even in the event that a suitable treatment is found, it is not likely to reach commercial markets in the United States for some time. The FDA requires experimental drugs to go through a three-stage process before approval for commercial use. In Phases I and II, drugs are tested to determine the safety of the drug and to collect important dosage data (Delaney, 1997). Phase III is designed to test the experimental drug in large numbers of patients to confirm the findings of Phases I and II and to compare the experimental treatment to standard treatments for the same disease. By necessity, this research process is slow and tedious, with only about one half of all clinical studies continuing through Phase III (Greene, 2002).
Despite the gradual process of investigating new drugs, scientists have continually worked to discover new treatment options for patients. Pharmaceutical researchers first uncovered drugs with angiogenic properties when developing drug therapies for tumor suppression. Tumors have the ability to grow their own blood vessels to supply nutrients to cancerous cells. Researchers found that destroying the blood's pathway would shrink the tumor substantially (Folkman, 1996). Antiangiogenic drugs work selectively on the endothelial cells of new capillaries, meaning they are not a threat to healthy tissues surrounding them (Dawson, et al., 1999). Another innate benefit of these treatments is that the cells targeted by the drugs do not build up resistance due to extremely low mutation rates of the capillaries' endothelial cells (Folkman, 1996).
One of the first drugs studied for its antiangiogenic properties during cancer research was thalidomide, a tranquilizer heavily prescribed outside of the United States during the 1960's (Burkholz, 1997). The FDA never approved the drug for use because the administration had doubts about the drug's safety. The doubts turned out to be well-founded; mothers who took thalidomide during the first trimester gave birth to about 8,000 infants with a distinct range of severely malformed limbs. Fortunately, this risk to fetuses would be negligible when using thalidomide to treat AMD because the patients are typically well beyond childbearing age. However, the results of the Age-Related Macular Degeneration and Thalidomide Study (AMDATS) report that thalidomide may not be a viable treatment option for AMD due to side effects (Scerra, 2001). The AMDATS was inconclusive as to the effectiveness of the drug because only 22% of the participants in the experimental group took thalidomide for the full 12 months of the study. Many participants reported that the side effects were too severe to continue taking the drug. In general, thalidomide has been associated with a long list of side effects in adults, including some as serious as irreversible peripheral neuritis (painfully numb hands and feet), low white blood cell count, blood sugar irregularity, thyroid problems, and irregular heartbeat (Burkholz, 1997). Because of the seriousness of the side effects as reported by participants, the AMDATS researchers advised that further research was not justified regardless of thalidomide's antiangiogenic properties (Scerra, 2001). As is often the case in science, not all experts will agree with this conclusion; the relative success of oncologists using thalidomide experimentally to treat cancer suggests that the side effects may be an obstacle that can be overcome (Thalidomide, 2001; Greene, 2000).
Another compound under investigation for the treatment of wet-type AMD is pigment epithelium-derived factor (PEDF). Studies on PEDF have shown that it may be a more effective CNV inhibitor than previously researched drugs (Hoglund, 2002). PEDF is a protein that researchers can extract from the human pigment epithelium, the nutrient rich layer directly behind the retina (Grossniklaus, 1999). This protein has the unique ability to both promote and inhibit CNV depending on the conditions within the eye. Research has shown that in an oxygen-rich environment, as is found in the healthy mammalian eye, PEDF was a natural inhibitor of CNV. When oxygen levels were low, as may commonly be the case in elderly patients, PEDF no longer inhibited CNV and new vessels grew to deliver the necessary oxygen (Dawson, et al., 1999). Although this concept has not yet been applied in a clinical setting, its research is promising. In a study that used human, mouse, and bovine corneas, PEDF inhibited CNV even in the presence of known angiogenesis agonists without affecting surrounding tissues (Dawson, et al., 1999). PEDF may prove to be a profitable line of research when developing new pharmaceuticals to prevent and combat wet-type AMD.
Other antiangiogenic drugs have been under research but have received less publicity. As with studies on other drugs, the results are mixed. These drugs include MK678, insulin-like growth factor-I, losartan, interferon alfa-2a, thrombospondin-1, angiostatin, and endostatin (Smith & Kopchick, 1997; Fumihiko, 2001; Dawson, et al., 1999). Information may become more readily available as research on these potential drug therapies continues.
Not all drugs under investigation for the treatment of wet-type AMD are antiangiogenic. In the summer of 2000, Akorn, Inc., announced that the company had submitted an Investigational New Drug Application to the FDA (AK-1003, 2000). The application was for AK-1003. This drug is different than the other investigational drugs because it is not a CNV inhibitor, but a drug intended for photodynamic therapy. This photodynamic drug differs from verteporfin. AK-1003 does not seal leaking capillaries like verteporfin photodynamic therapy does; it is designed to block blood flow from larger blood vessels that feed into the new capillary beds associated with wet-type AMD (MDP). This drug, if effective, would benefit AMD patients by providing more long-term improvements than the currently available photo-coagulation and photodynamic therapies offer.
While drug therapy for the treatment of wet-type AMD is still a thing of the future, the pharmaceutical research that will produce it is an important goal at present. Some researches suggest that AMD can be prevented by maintaining the healthy lifestyles promoted by health professionals for years&emdash;eat a well-balanced diet including leafy green vegetables (that provide leutin and zinc) and avoid smoking (Guttman, 2001; Levin, 1997). Because little data is available supporting these prevention techniques, scientists are borrowing concepts and compounds that have shown healing properties in tumor studies and using them to create new solutions for a growing elderly population. In the meantime, social service providers should begin to consider the likely impact of these new discoveries on society. For example, it is probable that the initial price of these new drugs when they reach commercial markets will be more than a senior citizen can afford with a fixed income (Folkman, 1996). It is also important to educate the population on the necessity of regular eye exams to detect problems early, a task many senior citizens avoid for financial reasons. New treatments will be virtually useless if the population that needs them most cannot access them.
AK-1003. (2000). Ophthalmology Times, 25, 5.
Burkholz, H. (1997). Giving thalidomide a second chance. FDA Consumer, 31, 12-14.
Dawson, D. W., Volpert, O. P., Gillis, P., Crawford, S. E., Xu, H. J., Benedict, W., & Bouck, N. P. (1999). Pigment epithelium-derived factor: A potent inhibitor of angiogenesis. Science, 285, 245-248.
Delaney, P. (1997). Understanding clinical trials from the patient's perspective. Retrieved February 19, 2002, from http://www.fda.gov/oashi/cancer/pdart.html
Folkman, J. (1996). Fighting cancer by attacking its blood supply. Scientific American, 275, 150-153.
Fumihiko, M. (2001). The role of choroidal haemodynamic abnormalities in the pathogenesis of age related macular degeneration. British Journal of Ophthalmology, 85, 1399-1400.
Gisele, S. & Bressler, N. M. (2001). Treatment of subfoveal choroidal neovascularization in age related macular degeneration: Focus on clinical application of verteporfin photodynamic therapy. British Journal of Ophthalmology, 85, 483-490.
Grossniklaus, H. E. (1999). Pigment epithelium-derived factor: A potent inhibitor of angiogenesis. American Journal of Ophthalmology, 128, 670.
Greene, K. (2000, July).Trials by Fire. Washington Techway. Retrieved February 11, 2002, from http://www.washtech.com/washtechway/1_14/lab/
Guttman, C. (2001), Drug research translates into aid for those with AMD: Pharmaceuticals, surgical options, nutrition considered for age-related macular degeneration. Ophthalmology Times, 26, 46-48.
Hoglund, T. (1999, November). PEDF shows dramatic potential for retinal degeneration. Retrieved on February 11, 2002, from http://www.blindness.org/html/science/wpedf2.html
Levin, L. A. (1997). Ophthalmology. The Journal of the American Medical Association, 227, 1881-1883.
Levy, S. (1999). Researchers suggest new way to treat macular degeneration. Drug Topics,143, 56.
MDP: Macular Degeneration Help Center. (n.d.). Retrieved February 11, 2002, from http://www.amd.org/print.asp?id=19302
Scerra, C. (2001). Side effects preclude thalidomide usefulness for AMD: Most frequent side effects were drowsiness, constipation, and peripheral neuropathy. Ophthalmology Times, 26, 30.
Smith, L. E. H. & Kopchick, J. J. (1997). Essential role of growth hormone in ischemia-induced retinal neovascularization. Science, 276, 1706-1709.
Thalidomide and antiangiogenic drugs in the treatment of multiple myeloma and blood cancers. (2001, July). Testimony of John W. Holaday, Ph.D., EntreMed, Inc., Rockville, MD before the Senate Appropriations Subcommittee on Labor, Health and Human Services and Education. Retrieved on February 11, from http://www.senate.gov/~appropriations/labor/testimony/Holaday.htm
Thompson, J. & Daniels, C. (1998). Wet-type macular degeneration. Radiologic Technology, 70, 85-88.
US Department of Commerce. (2001). Profiles of General Demographic Characteristics: 2000 Census of Population and Housing (United States). Washington, D. C.: Author.
Visudyne: Tx of select patients with wet form of age-related macular degeneration. (2000). Formulary, 35, 472.
Yam, P. & Netting, J. (1999). In Brief. Scientific American, 280, 22-24.