Macular Degeneration is characterized by a loss of central vision. There are two forms of Macular Degeneration "Dry" AMD and "Wet" AMD. Approximately 90% of patients have Dry AMD. Wet AMD can be treated with a class of drugs known as VEGF inhibitors. There are currently no approved therapeutics for Dry Macular Degeneration or the advanced stage of the disease known as Geographic Atrophy (GA).
A large and growing number of people are effected by AMD / Geographic Atrophy
There are more than 11 million individuals in the United States (US) and > 196 million worldwide living with some degree of AMD. Worldwide there are 5 million people living with GA and almost everyone with AMD will develop GA over time.
The underlying disease mechanism in dry AMD is controversial, nevertheless, a significant body of data supports an important role for LC and VLC PUFA. In healthy retina, LC and VLC PUFA account for about 50 % - 70% of all fatty acids. In aging humans and more notably in patients with AMD, levels of certain LC and VLC PUFA significantly decline.
Studies in human retinal pigmented epithelial cells (ARPE-19 Cells) demonstrate that knock down of ELOVL2 decreases the LC and VLC PUFA associated with aging and AMD. Similarly, transduction of ARPE-19 cells with ELOVL2 significantly increases the same LC and VLC PUFA. This suggest that 1) the declining levels LC and VLC PUFA associated with aging and AMD are mediated by ELOVL2 and 2) that increasing ELOVL2 expression can rescue retinal cells from this pathology.
To demonstrate the role of ELOVL2 in AMD pathology, an experimental model "knocking-down" the expression of ELOVL2 was developed in mice [functional knock-out( FKO). FKO mice showed characteristic pathologies associated with AMD including: marked acceleration of drusen formation, complement infiltration (data not shown), and reduced scotopic response compared to age matched wild type mice (WT).
Aged mice were treated with placebo or demethylation therapy (shown as 5- Aza). Following 12 weeks, the treated animals were tested for ERG response (Scotopic amplitude) and level of ELOVL2 gene expression. Demethylation therapy significantly increased ELOVL2 expression and scotopic response. These data suggest that restoration of ELOVL2 expression may slow or halt the decline of age related vision loss.