ADVANCES IN THERAPY FOR DRY AMD

Among the multitude of age-related conditions we face is age-related macular degeneration (AMD). The risk of AMD increases directly with age, and AMD is more common in white Americans and others of European descent, affecting more than 14% of those older than 80 years in this population. Age-Related Macular Degeneration (AMD), National Eye Institute, NIH. https://nei.nih.gov/eyedata/amd. Accessed March 28, 2016. If left untreated, AMD can progress from the early dry stage to the wet form and eventually to irreversible blindness. The Progression of Age-Related Macular Degeneration. AMD Blog. Dec 6, 2012. www.amdblog.org/maculardegeneration/ wet-amd/the-progression-of-age-related-macular-degeneration/. Accessed March 28, 2016.

Certain precautions can help mitigate the progression of AMD. Because obesity can increase the risk of AMD progression, good nutrition (including leafy vegetables, fruits, and foods rich in omega-3 fatty acids), and weight control are suggested, along with nutritional supplementation. Mogk LG. What treatments are available for dry macular degeneration? Vision Aware. American Foundation for the Blind. www.visionaware.org/info/your-eye-condition/age-related-macular-degeneration-amd/treatments-for-drymacular- degeneration/125. Accessed March 28, 2016. The multicenter, randomized, controlled AREDS clinical trial found that oral supplementation with a combination of antioxidants and zinc in patients with intermediate or advanced AMD in one eye reduced by 25% the risk of developing advanced AMD in the other eye over the next 5 years. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119(10):1417-1436. Avoiding smoking, controlling blood pressure, minimizing exposure to ultraviolet and harmful blue light, and attending periodic eye examinations can all contribute to decreasing progression of this disease.

Although these precautionary measures can help to decelerate AMD progression, often some form of therapy is ultimately required. This article describes therapeutic options in development that could pave the way for more effective management of dry AMD.

Dry AMD DEVELOPMENT and PROGRESSION

Cellular damage that accompanies aging often causes incomplete phagocytosis and breakdown of the outer segments of retinal pigment epithelium (RPE) cells. This can result in a buildup of the waste product lipofuscin in RPE cell granules. Lipofuscin is composed of membrane phospholipids, membrane proteins, visual cycle proteins, lipid-protein complexes, and retinoids. N-retinylidene-N-retinylethanolamine (A2E), one of the main chromophores residing in the lipofuscin granules, is responsible for lipofuscin-mediated phototoxicity. Preidt R. High-dose statins may ease macular degeneration for some. MedlinePlus. February 4, 2016. www.nlm.nih. gov/medlineplus/news/fullstory_157084.html. Accessed April 11, 2016., Boman N. Human visual cycle modulation for dry AMD. Retina Today. 2010;October:76-77. , Lampalizumab. Genentech: Our Pipeline. www.gene.com/medical-professionals/pipeline Accessed April 20, 2016.

Phospholipids of plasma membranes are rich in docosahexaenoic acid (DHA), a multisaturated omega-3 lipid acid. When eyes are exposed to sunlight in an environment rich in oxygen, DHA combines with phosphatidyletanolamine PE (PE-DHA) or phosphatidylcholine (PC-DHA) and by peroxidation splits into carbonic fragments, which, when combined with protein, make up carboxyethylpyrrole-protein adducts (CEPs). CEPs play a role in the inflammatory process associated with AMD. , Apellis: Pipeline. www.apellis.com/focus.html#pipeline Accessed April 20, 2016., Ambati J, Atkinson J, Gelfand B: Immunology of age realted macular degeneration. Nat Rev Immunol 2013, 13:438-51.

Malondialdehyde (MDA) is another molecule involved in AMD progression. Complement factor H binds MDA and can block MDA-induced proinflammatory effects. Zimura Anti-C5 Clinical Development. Zimura. Ophthotech. www.ophthotech.com/product-candidates/arc1905/ Accessed April 20, 2016.

During the visual cycle, a reaction between all-trans-retinal and membrane phospholipids causes the release of A2E, the photosensitization of which leads to the production of reactive oxygen species (ROS). This excessive oxidative stress can result in RPE cell dysfunction and, ultimately, apoptotic cell death. ,,Alzforum. Therapeutics. www.alzforum.org/therapeutics/gsk933776. Accessed April 11, 2016.,MacuClear. Future Treatments. http://macuclear.com/technology/future-treatments/. Accessed April 11, 2016.

The development of drusen, or yellow amorphic deposits in the space in between RPE and Bruch membrane, signals AMD progression. Drusen may be nodular (hard and discrete) due to a focal thickening of the RPE basement membrane or may be limited in separation of the RPE basement membrane from the Bruch membrane.

The disease can then progress into geographic atrophy (GA), a devastating complication of dry AMD. Drusen-associated GA can result in severe irreversible central vision loss due to the formation of dense scotomas, resulting in deficits in reading and other visual tasks. The decline in vision may be minor in the early stages if the foveas are spared, but later with central involvement it becomes severe. Visual acuity as measured on eye charts does not correlate well with GA lesions or progression, prompting the development of alternative end points for clinical research to test therapeutic agents. ,MacuClear. Technology. http://macuclear.com/technology/. Accessed April 11, 2016.

THERAPEUTIC STRATEGIES IN DEVELOPMENT

No treatment options for dry AMD are currently in the market, and patients are usually advised to follow the precautionary measures outlined above to help slow disease progression. Many companies and researchers are developing products to target dry AMD progression by exploiting a variety of modes of action. The table “Therapeutics Under Clinical Development for Dry AMD/GA” outlines small molecules, cell therapies, devices, and aptamers/peptides/antibodies in development for dry AMD treatment.

Intensive doses of statins, such as atorvastatin (Lipitor, Pfizer), rosuvastatin calcium (Crestor, AstraZeneca), and simvastatin (Zocor, Merck), were found to potentially clear the lipid debris that can lead to vision impairment in a subset of AMD patients studied in an early stage clinical trial. Additionally, controlling lipid cholesterol levels may be helpful in maintaining vision.

Therapeutics under clinical development for dry amd/ga

Visual cycle modulators such as emixustat HCl (Acucela) function by reducing the toxic accumulation of A2E during the visual cycle, potentially slowing the progression of AMD. This is brought about by targeting RPE65 isomerase, a key enzyme for the isomerization process of all-trans-retinol to 11-cis-retinol.

Inhibition of the complement system has been studied as a therapeutic approach, as local inflammation and complement activation are implicated in drusen formation.

A number of agents targeting the complement system are in development. Lampalizumab (Genentech) is a monoclonal antibody fragment targeting complement factor D. APL2 (Apellis Pharmaceuticals) is designed to broadly inhibit complement C3. LFG 316 (Novartis) is an antibody against the C5 portion of the complement pathway. Zimura (Ophthotech Corporation) is a chemically synthesized aptamer that inhibits complement factor C5.

GSK933776 (GlaxoSmithKline) is a humanized mouse IgG1 monoclonal antibody directed against the N-terminus of the A β peptide in drusen, with the aim of reducing the pool of toxic species in the retina. Its Fc region has been engineered to reduce FC-receptor binding and complement activation to weaken the antibody’s effector function and minimize the risk of side effects.

Restoration of choroidal blood flow is the proposed method of action of MC-1101 (MacuClear), using a combination of vasodilation, antiinflammation, and antioxidant properties; this could help to maintain the integrity of RPE cells and the Bruch membrane, thus preventing dry AMD from progressing to the wet form. ,

Some centers are exploring the repurposing of existing drugs for the treatment of AMD. Researchers at the University of Virginia are exploring whether the tetracycline antibiotic doxycycline, under development as Oracea, could help prevent photoreceptor cell loss and slow the progression of dry AMD. Clinical Study to Evaluate Treatment with Oracea for Geographic Atrophy (TOGA). ClinicalTrials. NIH. https:// clinicaltrials.gov/ct2/show/NCT01782989. Accessed April 20, 2016. Researchers at the University of California, San Francisco are investigating whether the antihyperglycemic drug metformin can slow DNA damage by reducing levels of ROS, thereby minimizing GA progression in patients with AMD. Metformin for the Minimization of Geographic Atrophy in Patients with AMD (METforMIN). ClinicalTrials. NIH. https://clinicaltrials.gov/ct2/show/NCT02684578. Accessed April 20, 2016.

Stem cell transplantation is another treatment modality being explored by numerous investigators. It is hoped that transplanted stem cells could help to regenerate the damaged RPE layer. Investigations under way include the following:

DEVICES

Several devices are also under development for the treatment of dry AMD. The photobiomodulation treatment protocol of the LT300 Light Delivery System (LumiThera) uses exposure to low levels of laser light or to light-emitting diodes emitting visible or near infrared light applied to the eye tissue to stimulate cellular processes, potentially leading to beneficial clinical effects. LumiThera. Photobiomodulation. Research. http://lumithera.com/research/. Accessed April 11, 2016.

Other devices exploit electrical stimulation in different ways. The Argus II (Second Sight Medical Products) bypasses defunct retinal cells and stimulates the remaining viable cells, inducing visual perception by converting images captured by a miniature video camera mounted on a patient’s glasses into a series of small electrical pulses. These signals are transmitted wirelessly to an array of electrodes implanted on the surface of the retina. The pulses are intended to stimulate the retina’s remaining cells, resulting in the perception of patterns of light in the brain. The patient then learns to interpret these visual patterns, thereby regaining some visual function. The system is controlled by software and is upgradeable, which may provide improved performance as new algorithms are developed and tested. Second Sight Announces First Age-Related Macular Degeneration Patient Receives the Argus II Retinal Prosthesis System as Part of Groundbreaking Study [press release]. Slyfar, CA: Second Sight Medical Products; July 22, 2015.

The Nova Oculus (The Eye Machine Canada) uses externally applied microcurrent electrical stimulation to administer precise amounts of electrical current. A battery-operated device delivers low-intensity electricity that increases blood flow to the surrounding tissue. As a result, the area being treated is better nourished, more oxygen gets to the tissue, and waste products are more efficiently removed. Enhanced Vision. Microcurrent stimulation study for dry AMD. www.enhancedvision.com/low-vision-info/ microcurrent-stimulation-study-for-dry-amd.html Accessed May 16, 2016.

The Rheohemapheresis device (University Hospital Hradec Kralove) is designed to improve microcirculation in order to halt the activity of dry AMD. The technique is based on constant flow separation of plasma through a cell separator and secondary filtration of plasma through a hollow-fiber membrane. Schreiner T, Rink S, Brunner R, Borberg H. First experience with a ready-for-use rheohemapheresis system. Transfus Apher Sci. 2001;24(2):125-128.

CONCLUSION

No currently available treatments can prevent vision loss in individuals with advanced AMD. Appropriate nutritional supplementation may delay or prevent the development of AMD. Numerous therapeutic options for dry AMD are under development.