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Research 01

Although it has not been proven that drusen cause ARMD, it is clear that, from a clinical standpoint, ARMD is rarely diagnosed in their absence. By gaining a more thorough understanding of how drusen form, therefore, the nature of the relationship between drusen and the pathogenesis of ARMD should become evident. Historically, our understanding of drusen formation has been hampered by the scarcity of information on their molecular composition. We have concluded, therefore, that the identification of their "fingerprint" at the molecular level is a necessary first step that will provide new insight into the cellular events and biochemical pathways involved in their formation.

Current Research on Drusen Origin and Molecular Composition

Research 02

During the past 5 years, scientists working at the Macular Degeneration Centers at the University of California, Santa Barbara and at the University of Iowa have obtained and published a partial profile (See Publications Archive) of the protein composition of drusen. Using antibodies to some of these proteins as biomarkers, together with high resolution microscopic instrumentation, some of the early cellular events that occur during the process of drusen formation are now beginning to be elucidated. Quantitative studies of gene expression are being used to identify the specific cell types responsible for manufacturing the proteins found in drusen, and expression arrays of up to 10,000 different genes are now being screened for changes in gene expression that may be involved in drusen formation.

One goal of these studies is to mimic the basic elements of drusen formation in cells grown in culture, or in a cell-free system. A second longer-term goal is to develop transgenic rodents that form drusen-like deposits similar to those that occur in the human eye. The development of new experimental approaches such as these should pave the way for the development of new treatments that delay the onset or prevent the accumulation of drusen, and thereby forestall the loss of central vision that accompanies ARMD.

Early Cellular Events involved in the Formation of Drusen

Research 03

Although drusen were first described almost 150 years ago, the earliest cellular events involved in their formation remain unknown. Historically, theories of drusen formation have emphasized the incorporation of RPE cell debris into drusen, abnormal secretions of the components that comprise Bruch's membrane, or disturbances in the transport of substances to and from the blood supply. Recently, CSMD scientists revisited this problem using laser scanning confocal immunofluorescence microscopy in conjunction with a set of molecular probes (i.e. antibodies) that attach to specific proteins, lipids, and other molecules found in drusen. Using this relatively new imaging technology, we identified novel substructural elements within drusen, and reconstructed a tentative sequence of cellular events that precede drusen formation. (Visual Simulation)

In general, our results reinforce the long-held view that RPE cell death over an extended period of time is the prelude to drusen formation. Prior to death, "compromised" RPE cells swell in volume and display a number of other classic signs of cellular injury. In some cases, these cells migrate away from the intact RPE monolayer into the sub-retinal space; in other instances, however, processes from adjacent cells migrate over the dying RPE cells, trapping the debris against Bruch's membrane. It is this trapped cellular debris that appears to be the initial "seeding" event in drusen formation, and that is followed by an attempt to encapsulate the exposed debris.

In other cells and tissues, it is well known that the chronic buildup and exposure of cellular debris in the microenvironment of cells can act as a local inflammatory stimulus. When that occurs, the body responds by activating a complex and highly orchestrated series of anti-inflammatory responses, all of which are designed to eliminate the source of inflammation. If the source is not eliminated, a chronic state of local inflammation occurs that may persist for years. Recent evidence strongly suggests that drusen formation may be a manifestation of this type of chronic local inflammation.

Implications for future treatments

Research 04

One important finding that has emerged from these studies is the fact that virtually all of the newly-identified proteins in drusen are functionally related to the process of inflammation or its aftermath. These results suggest, for the first time, that drusen may actually be a byproduct of chronic local inflammation (See Publications Archive) at the level of Bruch's membrane. They also provide the scientific rationale for the development and testing of new ARMD treatments that target the adverse effects of the chronic inflammatory cycle, rather than the primary defects in the RPE and/or photoreceptors.

This approach is not without precedent in other age-related diseases. In recent years, it has become apparent that other diseases of aging, including Alzheimer's disease and atherosclerosis, also have chronic local inflammatory components that can accentuate the effects of a primary pathogenic stimulus, whatever it may be. In the case of Alzheimer's disease, for example, there is now substantial clinical evidence that the sustained use of anti-inflammatory agents, such as ibuprofen, can delay the onset and slow the progression of Alzheimer's disease. By analogy, it is reasonable to propose that those individuals in the early stages of ARMD, particularly those with significant numbers of drusen in the macula, could benefit from long-term anti-inflammatory therapy that is designed to delay the onset of the more advanced symptoms of disease.

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Center for the Study of Macular Degeneration
University of California Santa Barbara
Last Modified 25-Jan-02