AMD Requires Better Understanding of Disease Pathogenesis

Demetrios G. Vavvas, MD, PhD (L) and Joan Miller, MD (R)

An article focused on the current understanding of neovascular age-related macular degeneration (wet AMD) and non-neovascular AMD (dry AMD) from Harvard Medical School's Department of Ophthalmology argued that in order to establish effective therapies for AMD, researchers need to better understand the processes underlying the development of the disease.

Lead author Joan Miller, MD, the current chair of Harvard Ophthalmology and a member of the Association of University Professors of Ophthalmology Board of Trustees, stated that several factors associated with AMD remain elusive and suggested that there is an "overwhelming need" to establish a structured classification system for AMD, as well as an "unmet clinical need" for "truly understanding the pathogenesis of the disease," which would aid in treatment developments.

Demetrios G. Vavvas, MD, PhD, co-director of Harvard Medical School's Ocular Regenerative Medicine Institute and an associate professor of ophthalmology at Harvard Medical School, also discussed the need for a standard classification system for both forms of AMD, stating that “it is important to standardize terminology because we are dealing with a complex, multifactorial, heterogeneous group of diseases.”

“If we are not clear on what all of us are discussing and we are not in agreement in what constitutes what, then our intellectual efforts are not going to be aligned and thus we are not going to have maximum progress in an efficient and timely manner,” Vavvas told MD Magazine.

This lack of consensus among clinicians may affect treatment of patients and progress of research on the disease, according to Miller, Vavvas, and colleagues.

The authors reported that a proposed classification scheme was suggested in 2013 by the Beckman Initiative for Macular Research Classification Committee, but it was based solely on fundus photography. Miller and Vavvas suggested that the lack of classification information based on other imaging modalities, of “the presence of subretinal drusenoid deposits,” and of attention to biological pathogenic processes makes the classification system less than ideal.

They believe that the most effective therapeutics emerge from an understanding of disease pathogenesis, a lesson researchers learned in developing anti-vascular endothelial growth factor (VEGF) therapies for wet AMD.

Vavvas said that an increased interest in the pathogenesis and associated biomarkers could “no doubt” lead to novel treatments for AMD and greater understanding of prevention and risk assessment, but that “we need to look head-on [at] the shortcomings of our past and current approaches [to] this disease.”

“[The biggest shortcoming] thus far has been that we are stuck with the old definition of what constitutes a disease, that came to us 100 years ago, prior to genetic and molecular biology knowledge. This old definition of the word 'disease' leads to 'basket' categorization that hides the myriad deferring root causes and leads to searches for panacea solutions for the elusive 'one cause,’” he said.

“Solutions that have wide applicability on patients despite deferring causes are only successful if they target shared processes,” Vavvas said. He noted that the price of going after processes rather than root causes is that we never solve the problem and must instead simply manage it with chronic administration.

For dry AMD, Vavvas suggested that the "one basket approach" be abandoned when it comes to looking for those root causes. “[Researchers] should understand more about the variability for the disease and design trials that take this into account,” he said.

Vavvas suggested that the management of wet AMD is primarily due to a deeper understanding of the pathogenic process of that form of the disease.

“To find similar success in dry AMD, we either have to uncover common shared process in cell death pathways regardless of the many factors (genetic and environmental) that lead to the dry degeneration and attack these pathways, or we have to better understand what causes the many forms of the disease and target the root problem on an individual basis,” he said.

He suggested that “Our drugs are not drugs that adjust the rheostat, but they are drugs that either block or activate. Thus, the chance of success is limited both because we fail to understand the root cause of dry AMD and because we fail to understand the process.”

Understanding the process, according to Miller, Vavvas, and colleagues will be vital for the next generation of therapies for dry AMD, and with a better understanding of the disease process, it is only a matter of time before more effective therapies emerge.