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Age-Related Macular Degeneration and How We May Treat It
As populations age globally, the incidence of age-related macular degeneration increases. To manage this, healthcare costs are expected to increase proportionately. Here, we discuss the eye disease and the potential treatments we can look forward to in the future.
by Vanessa Lunardi

Consisting of more than 1 million nerve fibres in the optic nerve, the eye is the second most complex organ in your body after the brain.1 For most of us, the eyes are how we perceive the world. It allows us to make out shapes and decipher colours, and send these visual cues to our brain, which turns this information into meaningful images.

As we age, our vision progressively gets weaker, and this can cause a series of eye diseases. One such retinal disease is age-related macular degeneration (AMD), which is caused by a multitude of factors, namely ageing, genetics, and environmental risk factors. It is the leading cause of blindness in individuals above 50 years old2 and has been estimated to affect about 288 million people worldwide by 2040.3

In this article, we discuss what is AMD, how it affects our eyesight, and what are the current and future treatments we can expect?

What is AMD?

Briefly, AMD is characterised by the accumulation of tiny yellow or white extracellular material, called drusen, along with progressive degeneration of photoreceptors and neighbouring tissues, eventually leading to central vision loss.

Though this disease is mostly detected in older individuals, scientists have identified several other risk factors of AMD, some of which, when modified, can help stabilise, or better yet, decrease AMD prevalence and alter disease progression.

The most consistent modifiable risk factors are smoking and diet, where according to a 2020 study,4 smokers are two to four times more likely to experience AMD, making it the primary modifiable risk factor of advanced AMD development. Other conditions such as hyperlipidaemia and hypertension may also be risk factors, albeit the level of evidence for these is lower. Additionally, AMD in one eye increases the likelihood that AMD will develop in the other eye.5

Other risk factors of AMD include ancestry, family history, and genetics. For example, a person above the age of 65, possessing Northern European ancestry, and whom have had a family history of AMD would be at greater risk of the disease. Through epidemiological and genetic studies, lipid genes have been implicated as AMD-associated genes due to an association between AMD and elevated high-density lipoprotein (HDL) levels. HDL cholesterol has been shown to be associated with an increased risk of AMD and is strongly linked to early AMD and drusen. This association of AMD with elevated lipid levels may account for the accumulation of lipid-rich drusen, which characterises early and intermediate disease stages.6 This raises another question, how exactly does AMD develop?

How Does AMD Affect Our Sight?

AMD affects part of the retina at the back of the eye called the macula, which is responsible for allowing clear, straight forward vision, by causing irreversible deterioration of photoreceptors. This results in visual distortions and eventual vision loss. Although scientists have yet to determine the exact cause of AMD, the age-dependent accumulation of uncleared cellular debris, known as drusen, on the Bruch’s membrane below the retinal pigment epithelium (RPE), is widely considered to be a hallmark of AMD.7 The RPE is the pigmented layer of the cells, located between the retina and the layer of blood vessels, called the choroid layer. The function of the RPE is to absorb light and transport nutrients to retinal cells. Studies suggest that the RPE is where macular degeneration starts to occur.8

Drusen is primarily composed of lipids and proteins, which can be seen as small white or yellowish deposits on the macula. While drusen deposits occur as a normal part of ageing, the growth in size and number of drusen can lend themselves to the deterioration of the macula and put an individual at risk for macular degeneration. With the accumulation of drusen in the Bruch’s membrane, along with other structural and biochemical changes associated with AMD pathogenesis such as persistent activation of the complement cascade and inflammation, the Bruch’s membrane thickens and becomes less permeable. Consequently, nutrient transport to the retina and waste exchange to the choroid are obstructed, leading to the thinning of the choroidal vasculature.

These effects, combined with the neuro-degenerative changes within the photoreceptor-RPE complex, result in pigmentary abnormalities of the RPE such as hypo- or hyperpigmentary changes. During early or intermediate stages of AMD, these changes can manifest as subtle visual disturbances among older adults. Over time, the combination of these factors can progress the disease into late stages, impair RPE and photoreceptor function altogether, and cause loss of central vision. However, it is worth noting that disease progression may vary across individuals depending on the type and stage of AMD.

Types of AMD

There are two types of AMD – wet or dry AMD – which can significantly affect disease progression. On the one hand, dry AMD is characterised by a slow progressive loss of visual function due to deterioration of the choriocapillaris, atrophic loss of the outer retina, and disruption and eventually death of the photoreceptor layer. Dry AMD is often associated with the accumulation of drusen aggregates. On the other hand, wet AMD involves the recruitment of immune cells to the damaged macula, where they secrete proinflammatory and proangiogenic cytokines, particularly vascular endothelial growth factor (VEGF).

VEGF exerts angiogenic effects by stimulating the proliferation and migration of endothelial cells. These newly grown blood vessels can leak fluid or burst, effectively disrupting the photoreceptor layer and distorting vision. Within days of weeks of the onset of wet AMD, some individuals may already experience visual impairment. In fact, although neovascular disease affects only about 20 per cent of patients with AMD, this clinical form is responsible for approximately 90 per cent of severe central vision loss caused by AMD.9

Stages of AMD

Ophthalmologists often categorise macular degeneration into its early, intermediate, or advanced stages based on the severity of symptoms including hypo- or hyperpigmentation, the number and size of drusen, and the presence of absence of choroidal neovascularisation.

In its early stages, dry AMD affects the RPE and secondarily destroys photoreceptors, whereas wet AMD affects the RPE but often involves degeneration and aberrant growth of the choriocapillaris and deep capillary plexus. During this stage, medium-sized drusen deposits can be seen upon eye examination. However, pigment changes are usually not present and vision loss rarely occurs at this stage of the disease.10 According to one study, only 15 per cent of those with small drusen at diagnosis, continued on to develop large drusen, which are noticeable during the intermediate or late stages of AMD.11 Moreover, AMD usually begins at 55 years of age or older. Therefore, there is a low risk of progression from early to late stage of AMD within five years after diagnosis.

During intermediate-stage AMD, large drusen, or multiple medium-sized drusen and/or pigment changes may be present in one or both eyes. RPE disturbances, taking in the form of pigment changes, may be found and lead to vision loss. Common symptoms during the intermediate stage may include subtle changes in vision, where black or grey spots obstruct the centre of patients’ visual field. Alternately, individuals may have trouble adjusting from a location with bright light to a dim area. However, most people do not experience any symptoms yet during this stage.

At the late-stage of AMD, ophthalmologist generally do not differentiate between dry and wet forms of AMD since either form can distort vision and/or cause vision loss. However, compared to the dry AMD, the wet AMD progresses much faster and is much more likely to cause vision loss. In particular, patients may lose their line of central vision. Although patients may retain their peripheral vision, they may encounter difficulty in recognising facts and objects.12

How Can We Manage AMD?

Currently, there is no efficacious treatment to prevent this degeneration. But over the past two decades, there have been major breakthroughs in wet AMD treatments, the most prominent of which are VEGF inhibitors. Anti-VEGF therapy has revolutionised the management of neovascular AMD by offering the potential for patients to maintain functional vision throughout their lifetimes. Since 2004, with the development and approval of pegaptanib sodium (Macugen), many other anti-VEGF therapies have emerged and become the primary method of treating neovascular AMD. Now, there are various VEGF-receptor targeting drugs including aflibercept, brolucizumab, and anti-VEGF antibodies, ranibizumab and ramucirumab.13

However, there are still a number of limitations and unmet clinical needs in the management of wet or neovascular AMD. For instance, most patients need to receive intravitreal injections as frequently as every month. Even if they do not require monthly injections, continuous and frequent follow-up is needed for surveillance, creating heavy treatment burden and unintended costs for both patients and providers. In addition, real-world data has shown that the visual acuity of patients do not improve with anti-VEGF treatments as well as reported in clinical trials, likely due to relative undertreatment. Moreover, anti-VEGF treatments primarily manage early wet AMD. As it stands, treatments for dry and late-stage AMD remain inadequate.7

Wet AMD

Having identified the burden of continuous anti-VEGF intravitreal injection therapies on patient well-being and disease management, scientists have endeavoured to develop extended drug delivery systems for anti-VEGF agents. In 2021, the first-of-its kind Port Delivery System (PDS), a novel device that may relieve the burden of repeated injections and frequent monitoring, was approved by the US Food and Drug Administration (FDA). PDS is a permanent, reusable drug reservoir that is surgically placed in the eye to store and slowly release anti-VEGF agents. Made of polysulfone, PDS includes a silicone septum that can be entered with a special needle to refill the device. During a refill, the needle can flush out the device while simultaneously refilling it with fresh ranibizumab. At the distal end of the septum, there is a semipermeable titanium membrane that allows for continuous passive diffusion of the drug from the higher concentration in the reservoir into the vitreous. Currently, PDS is in Phase III of clinical trials. With a planned total of 360 patients, the PDS, loaded with 100 mg/mL ranibizumab, is set to be refilled every 24 weeks. Compared to monthly intravitreal injections of 0.5 mg ranibizumab, this novel approach is expected to dramatically reduce patient visits.14

Another recent development is RGX-314, a novel, one-time gene therapy that delivers anti-VEGF agents. The procedure, which involves injecting an adeno-associated virus that carries the anti-VEGF gene under the retina, offers the potential to inhibit VEGF for years after surgery.13 At present, RGX-314 is undergoing Phase II clinical trials.15 Besides RGX-314, there are other gene therapy candidates in the pipeline. One such candidate is ADVM-022, a gene therapy vector designed for continuous delivery of aflibercept by a single in-office intravitreal injection. Based on Phase I trial results, ADVM-022 has demonstrated the potential to reduce treatment burden. While it has been associated with inflammation, research has revealed that it can be controlled well with steroid eye drops.16

Dry AMD

While there has yet to be an established treatment for dry AMD, several therapeutic approaches are being explored to reduce the rate of disease progression. These include drugs with antioxidative properties, cell-base therapies, and gene therapy, among many others.17

Since oxidative damage to the retina has been strongly linked with AMD, treatments that reduce the accumulation of reactive oxygen species have been proposed. According to a study involving more than 3,000 individuals, a daily dose of Beta-carotene, cupric acid, vitamin E, C, and zinc oxide was found to reduce the odds of developing advanced AMD in up to 34 per cent of subjects with high-risk characteristics. In addition, a follow-up of these participants over a 12-year period demonstrated that subjects who consumed the highest omega-3 fatty acids intake were 30 per cent less likely to develop central geographic atrophy and neovascular AMD.18

Retinal cell and tissue replacements are also emerging therapies for several retinal degenerative diseases including dry AMD. In particular, cell and tissue engineering research has been focusing on the preservation of photoreceptors by replacing damaged RPE sheets since it has been shown to slow the degeneration of photoreceptors and restore some visual functions.19 One method to reconstitute the RPE is by growing RPE cells on an appropriate scaffold. When grown on a scaffold, RPE cells have the potential to ameliorate visual impairment. Scaffolds help by organising the orientation of photoreceptor cells and ensuring that they are in close proximity with the RPE. Using scaffolds can also reduce the likelihood of RPE cells refluxing into the vitreous cavity which would lead to retinal detachment and blindness.

However, developing the right biomaterial to act as a scaffold is challenging. To ensure the safety of patients, scaffolds must be biodegradable, non-toxic, and thin enough to not affect the focal length of the eye. It must also be robust, yet flexible enough to survive the transplant procedure and conform the retina curvature respectively. Moreover, scaffolds should ideally provide a microenvironment that promotes the attachment, survival, and differentiation of RPE cells. Besides, further studies are needed to validate their safety and efficacy. Although scaffolds bearing stem cell-derived cells are now being tested in clinical trials to treat these retinal diseases and have demonstrated safety and modest improvements in vision, these trials have been too small to validate their efficacy. Scientists have also yet to determine the precise biological mechanisms by which these implants improve vision.20

Another treatment approach that is being explored is gene therapy, which is currently focused on sustaining the expression of proteins that reduce the growth of new blood vessels or antiangiogenic, and those that modulate the complement system. At present, there are active phase 1 trials using AAVCAGsCD59, an ocular gene therapy product, for dry and neovascular AMD. AAVCAGsCD59 can be injected into the eye and increase the expression of a compound that can help protect retinal cells by inhibiting the formation of the membrane attack complex which activates the complement system.21 Adeno-associated virus-mediated expression of certain factors that can attenuate the complement system are also being investigated for gene therapy.22

Conclusion

Evidently, these approaches are not without shortcomings and have yet to demonstrate definite therapeutic success, particularly for dry AMD. However, early clinical trials indicate that they show promise to help delay vision loss. Even a modest success against this devastating disease is expected to bring us another step closer towards developing a broad arsenal of effective treatment options. Therefore, research will continue to investigate the long-term safety and efficacy of these therapies.

References

  1. Addo, E., Bamiro, O. A., & Siwale, R. (2016). Anatomy of the eye and common diseases affecting the eye. In Ocular drug delivery: Advances, challenges and applications (pp. 11-50). Springer, Cham.
  2. SingHealth. (2018, November 21). Age-related macular degeneration. SingHealth. Retrieved from https://www.singhealth.com.sg/patient-care/patient-education/age-related-macular-degeneration
  3. Wong, W. L., Su, X., Li, X., Cheung, C. M. G., Klein, R., Cheng, C. Y., & Wong, T. Y. (2014). Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. The Lancet Global Health, 2(2), e106-e116.
  4. Heesterbeek, T. J., Lorés-Motta, L., Hoyng, C. B., Lechanteur, Y. T., & den Hollander, A. I. (2020). Risk factors for progression of age-related macular degeneration. Ophthalmic and Physiological Optics, 40(2), 140-170.
  5. Moon, B. G., Joe, S. G., Hwang, J. U., Kim, H. K., Choe, J., & Yoon, Y. H. (2012). Prevalence and risk factors of early-stage age-related macular degeneration in patients examined at a health promotion center in Korea. Journal of Korean medical science, 27(5), 537-541.
  6. Colijn, J. M., den Hollander, A. I., Demirkan, A., Cougnard-Grégoire, A., Verzijden, T., Kersten, E., ... & De la Cerda, B. (2019). Increased high-density lipoprotein levels associated with age-related macular degeneration: evidence from the EYE-RISK and European Eye Epidemiology Consortia. Ophthalmology, 126(3), 393-406.
  7. Christiansen, S. (2021, March 21). Macular Degeneration: Timeline of Vision Loss Progression. Verywell Health. Retrieved from https://www.verywellhealth.com/macular-degeneration-timeline-5069947
  8. Seddon, J. M. (2012, October 1). Macular Degeneration. Digital Journal of Ophthalmology. Retrieved from https://www.djo.harvard.edu/site.php?url=%2Fpatients%2Fpi%2F405
  9. Flaxel, C. J., Adelman, R. A., Bailey, S. T., Fawzi, A., Lim, J. I., Vemulakonda, G. A., & Ying, G. S. (2020). Age-related macular degeneration preferred practice pattern®. Ophthalmology, 127(1), P1-P65.
  10. National Center for Biotechnology Information. (2018, May 3). Age-related macular degeneration (AMD): Overview. National Center for Biotechnology Information. Retrieved April 5, 2022, from https://www.ncbi.nlm.nih.gov/books/NBK315804/
  11. Friberg, T. R., Bilonick, R. A., & Brennen, P. (2012). Is drusen area really so important? An assessment of risk of conversion to neovascular AMD based on computerized measurements of drusen. Investigative Ophthalmology & Visual Science, 53(4), 1742-1751.
  12. Khanna, S., Komati, R., Eichenbaum, D. A., Hariprasad, I., Ciulla, T. A., & Hariprasad, S. M. (2019). Current and upcoming anti-VEGF therapies and dosing strategies for the treatment of neovascular AMD: a comparative review. BMJ open ophthalmology, 4(1), e000398.
  13. Dunaief, J. (2021, August 20). Anti-VEGF treatments for wet age-related macular degeneration. BrightFocus Foundation. Retrieved from https://www.brightfocus.org/macular/article/anti-vegf-treatments-wet-age-related-macular
  14. Patel, S. N., Jenkins, T. L., Pieramici, D. J., & Regillo, C. D. (2019). Use of the port delivery system in AMD. Retina Today. Retrieved from https://retinatoday.com/articles/2019-may-june/use-of-the-port-delivery-system-in-amd
  15. Regenxbio Inc. (2021, October 20). RGX-314 Gene Therapy Pharmacodynamic Study for Neovascular Age-related Macular Degeneration (nAMD). ClinicalTrials.gov. Retrieved from https://clinicaltrials.gov/ct2/show/NCT04832724
  16. Charters, L. (2021, March 16). ADVM-022 offers sustained anatomic improvements in wet AMD. Ophthalmology Times. Retrieved from https://www.ophthalmologytimes.com/view/advm-022-offers-sustained-anatomic-improvements-in-wet-amd
  17. de Guimaraes, T. A. C., Varela, M. D., Georgiou, M., & Michaelides, M. (2022). Treatments for dry age-related macular degeneration: therapeutic avenues, clinical trials and future directions. British Journal of Ophthalmology, 106(3), 297-304.
  18. AREDS Research Group SanGiovanni John Paul [email protected] post. harvard. edu Agrón Elvira Meleth A Dhananjayan Reed George F Sperduto Robert D Clemons Traci E Chew Emily Y. (2009). ω–3 Long-chain polyunsaturated fatty acid intake and 12-y incidence of neovascular age-related macular degeneration and central geographic atrophy: AREDS report 30, a prospective cohort study from the Age-Related Eye Disease Study. The American journal of clinical nutrition, 90(6), 1601-1607.
  19. Jemni-Damer, N., Guedan-Duran, A., Fuentes-Andion, M., Serrano-Bengoechea, N., Alfageme-Lopez, N., Armada-Maresca, F., ... & Panetsos, F. (2020). Biotechnology and biomaterial-based therapeutic strategies for age-related macular degeneration. part II: cell and tissue engineering therapies. Frontiers in Bioengineering and Biotechnology, 1419.
  20. Rizzolo, L. J., Nasonkin, I. O., & Adelman, R. A. (2022). Retinal Cell Transplantation, Biomaterials, and In Vitro Models for Developing Next-generation Therapies of Age-related Macular Degeneration. Stem Cells Translational Medicine, 11(3), 269-281.
  21. Janssen Research & Development, LLC. (2021, May 28). AAVCAGsCD59 for the Treatment of Wet AMD. ClinicalTrials.gov. Retrieved from https://clinicaltrials.gov/ct2/show/NCT03585556
  22. Cashman, S. M., Gracias, J., Adhi, M., and Kumar-Singh, R. (2015) Adenovirus-mediated delivery of Factor H attenuates complement C3 induced pathology in the murine retina: a potential gene therapy for age-related macular degeneration. The Journal of Gene Medicine, 17(10-12), 229– 243.

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