Retinal degenerations that cause the loss of our sharpest (central) vision are often associated with excessive accumulation of lipofuscin within the retinal pigment epithelium (RPE). In ABCA4 (ABCR)-associated retinopathies, recent experimental studies have outlined specific pathogenetic steps causing this toxic accumulation; and therapies have been proposed to slow down the accumulation and delay the progression to blindness. The goal of the current program of research is to define precisely the micro- and macro-topography of lipofuscin accumulation and the rate of progression of this abnormality in patients with ABCA4 disease. This will lay the groundwork for targeted therapeutics designed to affect the natural history of this earliest detectable ABCA4 disease feature.
The first aim i s to quantify accumulation and clearance stages of lipofuscin longitudinally in patients with ABCA4 mutations; the hypothesis will be tested that visual dysfunction is first detectable during the clearance stage while the accumulation stage is subclinical.
The second aim i s to design and validate a simple outcome measure based on lipofuscin microtopography to be used in clinical trials designed to modify the natural history of ABCA4 disease sequence.
The third aim i s to perform pilot studies with two compounds that show potential for modifying the natural history of central or midperipheral ABCA4 disease. The questions posed in these aims can only be answered in human subjects using state-of-the-art quantitative ophthalmic techniques. The planned investigations are broadly relevant to many other hereditary maculopathies as well as to age-related macular degeneration (AMD) which partially shares with ABCA4 disease the pathophysiology of lipofuscin accumulation. The long-term goal of the research program is to unravel the pathophysiologic mechanisms in human hereditary retinal degenerations, contribute to the design of mechanism-specific therapies, and develop means to test their effectiveness. ? ?
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