Stephen F. Austin StateUniversity
Written February, 2002
In a society where technology has lengthened the average lifespan,age-related disorders present new treatment challenges. In the UnitedStates, senior citizens over the age of 65 account for 21% of thepopulation (US, 2001). This group of people will experience changesin their perceptual systems as they age, making it harder for them tofunction. Some of these changes will occur systematically andnaturally, while others will result from disease. In the case ofvision, age-related macular degeneration (AMD) is the leading causeof visual impairment in the elderly population (Levin, 1997). Expertsestimate that ten million senior citizens over the age of 75 sufferwith 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 fovearesulting 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 andprogresses more rapidly and painfully than dry-type AMD. This form ofAMD is responsible for severe visual impairment in 90% of all AMDcases 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 developwet-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 capillariesimpede vision by blocking incoming light, they also leak blood intothe surrounding tissues causing further damage. Currently, theFederal Drug Administration (FDA) has only approved two treatmenttechniques for wet-type AMD (Yam & Netting, 1999; Visudyne,2000). Researchers first developed photocoagulation, a procedureutilizing lasers to cauterize new capillaries and seal leaks.Unfortunately, this treatment is only useful in approximately 10% ofpatients who seek it and, while photocoagulation does decrease visionloss, the results are only short-term and the risk of damage tonearby photoreceptors is high (Gisele & Bressler, 2001; Yam &Netting, 2001; Thompson & Daniels, 1998). The most recentlyapproved treatment option is verteporfin photodynamic therapy, atwo-step treatment approved by the FDA in 2000 (Visudyne, 2000).Verteporfin is a light-activated drug that is first injected and thenactivated by thermal light to reduce new capillaries (Gisele &Bressler, 2001). Treatments not yet approved for commercial useinclude radiation therapy, surgical therapies, and pharmaceuticaltherapies (Thompson & Daniels, 1998).
The ideal tool against AMD is prevention, but the ideal treatmentof the future may be a drug therapy. Ophthalmologic research on AMDhas been very active in recent years, producing much more informationthan ever before (Guttman, 2001). Pharmaceutical research for thetreatment of wet-type AMD focuses primarily on antiangiogenic drugs,which would inhibit and sometimes reverse the effects of CNV. Resultsof clinical studies, however, show mixed results and some scientistsdo not see potential in the ongoing research (Gisele & Bressler,2001). Even in the event that a suitable treatment is found, it isnot likely to reach commercial markets in the United States for sometime. The FDA requires experimental drugs to go through a three-stageprocess before approval for commercial use. In Phases I and II, drugsare tested to determine the safety of the drug and to collectimportant dosage data (Delaney,1997). Phase III is designed to test the experimental drug inlarge numbers of patients to confirm the findings of Phases I and IIand to compare the experimental treatment to standard treatments forthe same disease. By necessity, this research process is slow andtedious, with only about one half of all clinical studies continuingthrough Phase III (Greene,2002).
Despite the gradual process of investigating new drugs, scientistshave continually worked to discover new treatment options forpatients. Pharmaceutical researchers first uncovered drugs withangiogenic properties when developing drug therapies for tumorsuppression. Tumors have the ability to grow their own blood vesselsto supply nutrients to cancerous cells. Researchers found thatdestroying the blood's pathway would shrink the tumor substantially(Folkman, 1996). Antiangiogenic drugs work selectively on theendothelial cells of new capillaries, meaning they are not a threatto healthy tissues surrounding them (Dawson, et al., 1999). Anotherinnate benefit of these treatments is that the cells targeted by thedrugs do not build up resistance due to extremely low mutation ratesof the capillaries' endothelial cells (Folkman, 1996).
One of the first drugs studied for its antiangiogenic propertiesduring cancer research was thalidomide, a tranquilizer heavilyprescribed outside of the United States during the 1960's (Burkholz,1997). The FDA never approved the drug for use because theadministration had doubts about the drug's safety. The doubts turnedout to be well-founded; mothers who took thalidomide during the firsttrimester gave birth to about 8,000 infants with a distinct range ofseverely malformed limbs. Fortunately, this risk to fetuses would benegligible when using thalidomide to treat AMD because the patientsare typically well beyond childbearing age. However, the results ofthe Age-Related Macular Degeneration and Thalidomide Study (AMDATS)report that thalidomide may not be a viable treatment option for AMDdue to side effects (Scerra, 2001). The AMDATS was inconclusive as tothe effectiveness of the drug because only 22% of the participants inthe experimental group took thalidomide for the full 12 months of thestudy. Many participants reported that the side effects were toosevere to continue taking the drug. In general, thalidomide has beenassociated with a long list of side effects in adults, including someas serious as irreversible peripheral neuritis (painfully numb handsand feet), low white blood cell count, blood sugar irregularity,thyroid problems, and irregular heartbeat (Burkholz, 1997). Becauseof the seriousness of the side effects as reported by participants,the AMDATS researchers advised that further research was notjustified regardless of thalidomide's antiangiogenic properties(Scerra, 2001). As is often the case in science, not all experts willagree with this conclusion; the relative success of oncologists usingthalidomide experimentally to treat cancer suggests that the sideeffects may be an obstacle that can be overcome (Thalidomide,2001; Greene,2000).
Another compound under investigation for the treatment of wet-typeAMD is pigment epithelium-derived factor (PEDF). Studies on PEDF haveshown that it may be a more effective CNV inhibitor than previouslyresearched drugs (Hoglund,2002). PEDF is a protein that researchers can extract from thehuman pigment epithelium, the nutrient rich layer directly behind theretina (Grossniklaus, 1999). This protein has the unique ability toboth promote and inhibit CNV depending on the conditions within theeye. Research has shown that in an oxygen-rich environment, as isfound in the healthy mammalian eye, PEDF was a natural inhibitor ofCNV. When oxygen levels were low, as may commonly be the case inelderly patients, PEDF no longer inhibited CNV and new vessels grewto deliver the necessary oxygen (Dawson, et al., 1999). Although thisconcept has not yet been applied in a clinical setting, its researchis promising. In a study that used human, mouse, and bovine corneas,PEDF inhibited CNV even in the presence of known angiogenesisagonists without affecting surrounding tissues (Dawson, et al.,1999). PEDF may prove to be a profitable line of research whendeveloping new pharmaceuticals to prevent and combat wet-typeAMD.
Other antiangiogenic drugs have been under research but havereceived less publicity. As with studies on other drugs, the resultsare mixed. These drugs include MK678, insulin-like growth factor-I,losartan, interferon alfa-2a, thrombospondin-1, angiostatin, andendostatin (Smith & Kopchick, 1997; Fumihiko, 2001; Dawson, etal., 1999). Information may become more readily available as researchon these potential drug therapies continues.
Not all drugs under investigation for the treatment of wet-typeAMD are antiangiogenic. In the summer of 2000, Akorn, Inc., announcedthat the company had submitted an Investigational New DrugApplication to the FDA (AK-1003, 2000). The application was forAK-1003. This drug is different than the other investigational drugsbecause it is not a CNV inhibitor, but a drug intended forphotodynamic therapy. This photodynamic drug differs fromverteporfin. AK-1003 does not seal leaking capillaries likeverteporfin photodynamic therapy does; it is designed to block bloodflow from larger blood vessels that feed into the new capillary bedsassociated with wet-type AMD (MDP).This drug, if effective, would benefit AMD patients by providing morelong-term improvements than the currently available photo-coagulationand photodynamic therapies offer.
While drug therapy for the treatment of wet-type AMD is still athing of the future, the pharmaceutical research that will produce itis an important goal at present. Some researches suggest that AMD canbe prevented by maintaining the healthy lifestyles promoted by healthprofessionals for years&emdash;eat a well-balanced diet includingleafy green vegetables (that provide leutin and zinc) and avoidsmoking (Guttman, 2001; Levin, 1997). Because little data isavailable supporting these prevention techniques, scientists areborrowing concepts and compounds that have shown healing propertiesin tumor studies and using them to create new solutions for a growingelderly population. In the meantime, social service providers shouldbegin to consider the likely impact of these new discoveries onsociety. For example, it is probable that the initial price of thesenew drugs when they reach commercial markets will be more than asenior citizen can afford with a fixed income (Folkman, 1996). It isalso important to educate the population on the necessity of regulareye exams to detect problems early, a task many senior citizens avoidfor financial reasons. New treatments will be virtually useless ifthe population that needs them most cannot access them.
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