|Year : 2011 | Volume
| Issue : 1 | Page : 2-5
Pharmacological treatment of dry age-related macular degeneration (AMD)
George C.Y Chiou
Institute of Ocular Pharmacology, Texas A&M Health Science Center, College Station, TX, USA
|Date of Web Publication||1-Dec-2011|
George C.Y Chiou
Institute of Ocular Pharmacology, Texas A&M Health Science Center, 303 Reynolds Medical Building, College Station, TX 77843
Source of Support: None, Conflict of Interest: None
As the population grows older each year, age-related macular degeneration (AMD) is becoming the leading eye disease resulting in blindness. Although some drugs are available for the treatment of wet AMD, no drug is currently available for dry AMD. Actual research is taking place to invent novel drug for the treatment of dry AMD and the hurdles of the R&D are reviewed. Literature search and review were conducted to identify various ideas to treat dry AMD and to overcome the difficulties of developing clinical end points for developing the new drugs. Some promising drug candidates had been identified and clinical end points of drug efficacy determination had been collected. With the proof of new concepts and clinical end points available, the hope is high to expect some new novel drugs be put in the market sometime in the future.
Keywords: choroidal blood flow facilitation, dry AMD, metabolic wastes, pharmacological agents
|How to cite this article:|
Chiou GC. Pharmacological treatment of dry age-related macular degeneration (AMD). Taiwan J Ophthalmol 2011;1:2-5
| 1. Introduction|| |
Age-related macular degeneration (AMD) is a debilitating disease on central vision in patients over 50 years old., It was first described in the medical literature as a symmetrical central cho-rioretinal disease occurring in senile individuals. It was not until 1980 that AMD was regenerated to be a significant cause of blindness in the United States. Even though the prevalence of AMD is highest among Caucasians in Western countries, the prevalence among Asians is equallyas high as Caucasians in AMD development (Wong et al, 2006). In 2004, the World Health Organization estimated that there are 14 million individuals worldwide suffering from blindness or are severely visually impaired due to AMD. As the population in the Western world is growing older, the incidence of losing the ability to read and to drive due to AMD is becoming increasingly apparent. An analysis in 2004 reported that among Americans over the age of 40 years, AMD and/or geographic atrophy were present in at least one eye in 1.5% of the population. By the year 2020, there may be a 50% increase in the incidence of AMD. predicted that as a result of the increasing prevalence of AMD, the number of blind people in the United States could increase by as much as 70% by 2020. Given the enormous impact of AMD on the aging population, much public attention and research has been focused on this condition in the past decade.
AMD initially occurs in a “dry” form with pathological changes in the retinal pigment epithelium (RPE) and drusen accumulation and can progress to geographic atrophy (90%) and/or the “wet” form of AMD (10%) with choroidal neovascularization (CNV). The breakdown of Bruch’s membrane under RPE serves as an entrance for new and immature choroid vessels to grow into the subretinal space that leads to the formation of CNV.6,,, CNV can leak fluid and hemorrhage in the subretinal space resulting in blurry vision, visual distortion and sudden loss of vision. If left untreated, these can progress to form an organized fibrous scar, known as a disciform scar, which results in irreversible central vision loss.
| 2. Etiology and pathogenesis of dry AMD|| |
Drusen is a typical clinicopathologic entity in dry AMD, which is caused by the changes of RPE and Bruch’s membrane (BRM). Dru-sen is deposited in between the basement membrane of RPE and BRM or external to BRM. The prevalence and severity of drusen formation in the eyes are linearly related to the progression of AMD. Oxidative stress has long been linked to age-related degenerative diseases and is implicated in the pathogenesis of AMD. An important source of oxidative damage is likely to be the photoreactive pigments that progressively accumulate and constitute the lip- ofuscin of RPE cells.,
Similar to drusen, basal laminar deposit (BLD) is another typical sign of AMD development and is led by extracellular deposit. BLD is located between the cell membrane of RPE and its basement membrane., The pathogenesis of BLD could be enhanced by a high fat/cholesterol diet. The accumulation of lipid particles in BRM is often associated with vascular endothelial growth factor (VEGF) expression and ultimate development of CNV in wet AMD.
Inflammation and a compromised immune system are also attained in the pathogenesis of dry AMD. As a result, anti-inflammatory agents such as steroids are frequently used for the treatment of dry AMD. More specifically, complement components such as C3 and C5 are constituents of drusen in AMD patients. Others, such as interleukin-1, interleukin-6 and tumor necrosis factor, are also implicated in the development of dry AMD. Thus, interleukin-1 blockers have also been used in dry AMD animal models.
In addition to age, high-fat diet, light oxidation and inflammation, smoke, alcohol and gene factors are also frequently questioned. Epidemiologic studies have indicated that cigarette smoke is the single greatest environmental risk factor for both dry and wet AMD. Mice experiments with inhaled cigarette smoke resulted in the formation of RPE deposits, thickening of BRM and accumulation of deposits, within the BRM membrane. In another experiment mice were fed with nicotine in drinking water, and the results showed that nicotine increased the size and severity of experimental CNV formation.
The influence of alcohol on the development of CNV in wet AMD was studied by. The results showed that the activity of fatty acid ethyl ester synthase activity increased 4-fold in the choroid of alcohol-treated rats compared with controls. Furthermore, the amount of ethylesters produced in the choroid was 10-fold higher in alcohol-fed rats than controls. The size of CNV formation induced by laser treatment increased by 28% due to alcohol treatment.
In addition to environmental factors, genes also play an important role in the development of dry AMD. Thus, some animal models used for AMD studies include transgenic mice treated with blue–green light.
There are some diseases which are similar to AMD. They include Stargardt macular dystrophy (STGD) and Sorsby’s fundus dystrophy (SFD). STGD is characterized as dry AMD by accumulation of high level of lipofuscin in the RPE. It precedes to degeneration of photocells in the macular and atrophy of RPE., SFD is a rare autosomal dominant disorder that results in degeneration of the macular region, which leads to rapid loss of central vision similar to wet AMD.
Most importantly, the choroidal blood flow of dry AMD and STGD is compromised and significantly lower than normal eyes., As a result, all metabolic wastes produced from oxidation, inflammation, aging, complement components, cytokines, cigarette smoke, nicotine, high lipid, and alcohol, etc., are accumulated in RPE cells and BRM which trigger dry AMD and eventually lead to wet AMD or geographic atrophy. By contrast, nutrient supply to BRM, RPE, and photocells at the macula are markedly reduced which facilitate the worsening of dry AMD.
| 3. Treatment of dry AMD|| |
Treatment of AMD was originally focused on wet AMD, and dry AMD was left untreated because no effective method was available. Physical therapy of wet AMD includes but is not limited to laser photocoagulation,,,, transpupilary thermotherapy, radiotherapy. Unfortunately, none of these were efficacious and all were receded to second-line choice of treatment at present when pharmacological therapy becomes available.
Because CNV formation is the major source of wet AMD development, early research for wet AMD treatment has been focused on antiangiogenesis similar to cancer treatment. These agents include steroids such as triamcinolone and anecortave acetate,, thalidomide, and interferon.
Drugs which can change the construction of the extracellular matrix or change the balance of matrix metalloproteinases and tissue inhibitors of metalloproteinases may also have an effect on the angiogenesis process. These drugs are called extracellular matrix modifiers and are still in the experimental stage of development.
Gene therapy by using subretinal injection of adenoviral or adeno-associated viral vectors has been used to transform the RPE into a component for sustained local delivery of a drug or a gene in experimental CNV animals., These are drugs of the future for wet AMD.
Although fruitful progress has been made in the treatment of wet AMD, the treatment of dry AMD is still sparse. Currently, there is no single drug available for the treatment of dry AMD. As 90% of the AMD patient population is in the dry stage, currently there is active research being carried out at different stages of research and development.
Most research and development of dry AMD is concentrated on the prevention of metabolic waste production with limited success, mainly because the production of metabolic wastes come from numerous sources, including oxidation, aging, complement components, cytokines, inflammations, etc. Thus, a complete inhibition of one branch of all pathogens can suppress the progression of dry AMD at only around 20% at best, which is classified as borderline efficacy only. In addition, metabolic wastes are normal products of physiological procedures of the body and complete inhibition of normal metabolism could result in other various pathological side effects. Furthermore, visual acuity does not change significantly during the progression of dry AMD; thus, selection of proper endpoints to evaluate drug efficacy in clinical trials are very difficult, if not impossible.
Antioxidants are agents that are studied most extensively. Lutein and zeaxanthin are two major carotenoids in the human macula and retina. They are deposited at an up to 5-fold higher content in the macular region compared with the peripheral retina. Owing to the antioxidant properties of carotenoids, lutein and zeaxanthin are considered to have the ability to protect and/or delay the progression of dry AMD.
The AREDS (Age-Related Eye Disease Study) report (2001) described that food supplements that contain carotenoids, antiox-idants vitamins A, C, and E, plus minerals, such as zinc, showed a 25% decrease in the rate of progression to aggressive AMD among high risk patients. The findings of the LAST (Lutein Antioxidant Supplementation Trial; report also support a possible therapeutic role of lutein in AMD treatment. However, critical evidence of therapeutic efficacy has not been established.
A novel idea to solve the problem has recently been developed by Chiou in the Texas A&M Health Science Center. The idea is based on the risk factor of dry AMD as a reduction of choroidal blood flow,,, which lead to the accumulation of all waste products regardless of where they come from, including aging, oxidation, inflammation, complement components, cytokines, etc. Thus, instead of solving problems individually by using inhibiting/ blocking agents of aging, oxidation, inflammation, complement components and cytokines, all waste products will be eliminated by choroidal circulation. Further nutrients will be replenished to BRM, RPE, and photocells via improved choroidal circulation in the macula to improve vision.
Numerous agents that can increase choroidal blood flow in rabbit eyes have been tested in dry AMD animal models. Among them, some were found to be rather efficacious in inhibiting the development of dry AMD. They include, but are not limited to, hydralazine,,, tetramethylpyrazine,,, flavone,, nar-ingenin,, apigenin, interleukin-1 blockers, and D-timolol.
Reduction in choroidal blood flow causes deposition of extracellular proteins, lipids, and metabolic wastes in the form of basal deposits within BRM and of drusen in between BRM and RPE. The progressive deposition of lipid in BRM results in the degeneration of elastin and collagen, and ultimately calcification. The combination of elevated choriocapillaris pressure, expansion of VEGF, and break in calcified BRM causes development of CNV and wet AMD. Vasoactive agents which can facilitate choroidal blood flow are believed to prevent the progression of dry AMD and are the major focus of current research.
| 4. Clinical protocols for anti-dry AMD drug studies|| |
There are at least two major obstacles which hinder the development of drugs for the treatment of dry AMD. First, a long time period is required to observe progression of the disease,, which discourages researchers as well as investors to become involved. Second, the clinical endpoints to show drug efficacy other than visual acuity are difficult to determine and are not yet approved by the Food and Drug Administration (FDA). There are several promising methods under consideration and if approved by the FDA, they can facilitate drug evaluation and development in the future.,
Dry AMD is a unique chronic disease whereby visual acuity does not change much during the early stage of disease progression. Its change does not match the worsening of visual acuity until the late stage of the disease. Consequently, the efficacy of drug actions to treat dry AMD is impossible to assess, based on the changes of visual acuity. This is very different from the assessment of wet AMD drug actions, as the progression of wet AMD is parallel to the loss of visual acuity. Prolongation of dark adaptation is closely correlated to the severity of AMD.,, Dark adaptation is strongly impacted in AMD long before there is any significant loss of visual acuity. Thus, measurement of dark adaptation is one of the feasible ways to measure drug efficacy for the treatment of dry AMD. The commercially available prototype dark adaptometer (AdaptRx, Apeliotus Technologies, Inc., Atlanta, GA, USA) is now available.
Accumulation of the number and size of drusen is another parameter used to measure the progression of dry AM. Because the change in drusen deposits is very slow and difficult to note subjectively, Matched Flicker (EyeIC.com) has been developed to record the changes objectively and precisely. Basically, the precise high-tech use in space science to record minute changes occurring in the sky at any time period has been applied to measure the changes of drusen occurring in the fundus of the same eye. Basically, two retinal images of the same eye from virtually any source can be loaded into Matched Flicker and the changes can be brought to life and observed as easy-to-detect motion. Because very minute changes in drusen accumulation can be detected with the machine precisely and objectively, it shortens the time to detect changes in drusen deposit compared with the inaccurate subjective observation with the naked eye in the past. As a result, the clinical study of drug efficacy in slowing down the rate of drusen accumulation can be easily accomplished.
As indicated previously, the change of visual acuity, although most important, is minute and difficult to measure during early and intermediate stages of dry AMD. However, it is the only measurement approved by the FDA for the study of drug efficacy during late stage/wet stage of AMD. A useful tool for determining patients’ vision-related function has been developed to allow the improved sensitivity for detection of even a slight change in visual acuity in the stage of early and intermediate stages of dry AMD. The device is called NEI VFQ-25 (National Eye Institute Visual Function Questionaire-25) which is responsive to changes in patients’ visual acuity and is able to differentiate between patients who are responders and nonresponders.
Although NEI VFQ-25 measures patients’ subjective evaluation of their visual function and how impairment in vision affects their lives, it is reliable, valid, and responsive compared with the standard measure of vision used in clinical trials such as BCVA (Best Corrected Visual Activity) using standardized ETDRS (Early Treatment of Diabetic Retinopathy Study) vision protocols. The NEI VFQ-25 showed a large separation between the groups with improved BCVA (gained >15 letters), stable BCVA (gain or lost 15 <letters), and worse BCVA (lost >15 letters). It may also provide a more broad assessment of the visual function on lifestyle- and vision-dependent activities than BCVA alone. On average, the 25-letter or better improvement in BCVA corresponds to an increase in the NEI VFQ-25 score of 8.2 in the MARINA Trial (Minimally Classic/Occult Trial of Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD).
Although not all dry AMD would develop into wet AMD, 10–15% of dry AMD would eventually be converted into wet AMD. Thus, prevention of dry AMD to be converted into wet AMD is also a measurement of drug action to suppress the progression of dry to wet AMD. As only 10–15% of dry AMD would be converted into wet AMD, a large number of patients are needed to study the difference in drug treatment. Briefly, ideal clinical endpoints are urgently needed for the measurement of the efficacy of new drugs for the treatment of dry AMD. There are at least four methods under consideration by the FDA. If approved, it can shorten the measurement of drug efficacy to save time, effort, and funds.
| 5. Investigative drugs under development|| |
There are numerous drugs under development at various stages. Some were discontinued as they were found to be ineffective. Those which are still under development include, but are not limited to, MC1101 (MacuClear) to improve choroidal blood circulation to excrete metabolic wastes from, and provide nutrients to, RPE, BRM, and photocells; OT-551 (Othera) as an antioxidant to reduce drusen formation; Fenretinide (Sirion) as an antineoplastic to reduce lip-ofuscin accumulation; Anecortave acetate (Alcon) as an angiostatic agent to suppress conversion of dry AMD to wet AMD; CNTF (ciliary neurotrophic factor;Neurotech) for atrophic macular degeneration; POT-4 (Potentia) as a complement inhibitor to shut down the complement activation system that leads to local inflammation; Rapamycin (MacuSight) as an immune suppressant similar to steroids as an anti-inflammatory agent; and AREDS-2 (NEI) as an antioxidant.
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