Research Drives AMD Treatments Toward Targeted Therapies

Age-related macular degeneration (AMD) is the leading cause of blindness for those 55 years and older. As the population ages — not only in the U.S. but worldwide — there is a greater sense of urgency to discover therapies that can effectively address what will be an all-too-common health concern. Advances in research have spurred the introduction of some treatments, but even those that have been in circulation for some time and proven widely effective are not effective for everyone. Given the multiple pathways to AMD, with contributions from both genetic and environmental risk factors, targeted therapies will be the way of the future.

Not all cases of AMD are created equal

AMD takes on one of two forms: wet AMD or dry AMD. Wet AMD, or choroidal neovascularization, is less prevalent but also treatable. It is characterized by abnormal blood vessel growth into the retina, and that intrusion and leakage of blood into the retina disrupt the photoreceptors, which causes a disruption to vision. Patients may notice that once straight lines appear wavy, or they could have a blank spot in their central vision. The onset of symptoms is relatively rapid, but treatments can effectively promote a regression of blood vessels and help restore vision. Only about 10% of patients with AMD have this treatable form.

Dry AMD, on the other hand, occurs in more than 80% of patients and no time-tested treatments exist. This slow progressing disease involves the death of the retinal pigment epithelium (RPE), cells that support the health of the light-sensing photoreceptors by serving as a conduit for nutrients and oxygen from the outer retinal blood supply. Importantly, the RPE cells have no regenerative potential, so once this critical support system is lost, photoreceptors are prone to damage and loss.

Typically, patients learn they have the condition at regular eye exams, where an ophthalmologist may identify drusen (tiny bits of debris in the back of the eye), or when they begin experiencing impaired vision, at which point they are often in an advanced stage, or geographic atrophy (GA). The FDA has only recently approved two therapies intended for dry AMD, but their efficacy for a broad patient population has not yet been determined.

Identifying pathways is key

Both new therapies for dry AMD target the complement pathway. Part of the immune system and present in all tissues, the complement pathway surveys for invading pathogens and removes them, which is a good thing. It can go into overdrive or behave erratically, however, which can result in the destruction of good tissue. New treatments are formulated to keep the complement pathway in check and inhibit it from destroying cells in the eye, as this destruction is a mechanism for dry AMD.

While the new therapies are promising, they target just one of potentially many mechanisms for the condition. Researchers have successfully used genetics to identify specific pathways that appear to increase the risks of developing dry AMD, with dozens of different genes found to be potential culprits. In just the past decade or so, at least six different pathways that could contribute to the onset of dry AMD have also been uncovered.

One relatively recent development includes the discovery that the mitochondria, the cell’s center for generating energy, is compromised in the RPE cells early in the disease, which could indicate a potential pathological event contributing to dry AMD onset. Cell culture models are replicating the findings, and further investigation points to a specific population that carries the complement factor H risk allele and appears more susceptible to mitochondrial disruption.

In addition to exploring the mitochondrial factor, researchers are working to understand other risk alleles and the biology behind them. By understanding the biological processes that go awry early on in dry AMD, investigators should be able to develop more targeted therapies. Further, coupling scientific research with the frontline experience of ophthalmologists can help to identify and understand which pathway is impacting a particular patient so that treatment can be tailored to achieve the best possible outcome. Even with wet AMD, the available treatments are not effective in all patients, which suggests that the remedies are overlooking a key mechanism in some individuals.

Research progresses amidst challenges

The scientific community has persisted in advancing dry AMD research, although this particular disease presents some challenges. Genetics is only one piece of the puzzle. Environmental factors also play a role for individuals, as a history of smoking or poor diet, for instance, can elevate the danger of developing dry AMD. And because AMD is an age-onset disease, it may be near impossible to pinpoint what, in a 50- or 60-year lifetime, set an individual on their path to disease.

Animal models representative of the human condition are highly valuable in medical research, but AMD researchers are hard-pressed to find a close approximation due to the unique features of the human eye and the contribution of aging. To maintain momentum in their field, AMD researchers are turning to different types of cultured cells. Induced pluripotent stem cells (iPSCs) are a somewhat recent innovation and have shown considerable potential.

Mature cells are taken from an adult, and those cells have their development reversed to the point at which they become like a fetal cell. At that juncture, they can be differentiated into any cell in the body, including RPE cells, and be studied in a dish to learn AMD’s underlying pathophysiology and identify potential treatments. Future progress with iPSCs include using patient-specific cells to identify the optimal treatment for each patient, possibly opening the door to personalized medicine — the Holy Grail of medicine by some estimations. 

For AMD researchers, one of the most valuable sources for IPSCs are eye banks, where people have donated their eyes to medical research. Scientists have made major discoveries from accessing and comparing eyes of those individuals with AMD to those without the disease. In addition to studying the tissues itself, researchers can generate critical iPSCs from the donations, furthering the impact of the donation and moving investigators closer to new, effective therapies.

Pressing ahead with intention

Recent FDA approval of dry AMD therapies is encouraging, but the work is not done. Considering the genetic and environmental variations in the millions of patients currently and potentially coping with the disease, more than a one-size-fits-all approach will be needed to transform lives for the better. Researchers must continue to ask critical questions about cellular changes associated with aging, factors that influence pathology, cellular responses to disease, and the potential to protect against pathologic changes. As such mysteries are unraveled, the scientific community will move closer to discovering groundbreaking therapies for this widespread, life-altering condition.