The macula is the central portion of the retina, the thin layer of light sensitive tissue located at the back of the eye. The macula is used for central vision, so when the cells of the macula deteriorate, central vision is lost along with the ability to perform tasks such as reading, writing, driving, recognizing faces.
This results in "macular degeneration", a disease that principally affects the elderly and is the leading cause of blindness in the western world. Younger patients can also be affected by genetic forms of macular degenerations such as Stargardt disease, vitelliform (or Best) macular degeneration (VMD), Sorsby's fundus dystrophy, and malattia leventinese (Doyne honeycomb or dominant radial drusen).
Hundreds of genes have been associated with macular and retinal degenerations. Individual types of photoreceptor degeneration are distinguished by their modes of inheritance, patterns of visual loss, clinical appearance of the retina and defective gene(s) involved.
Photoreceptor death may take years to decade after birth and the mechanism of degeneration are poorly understood in most cases. However, several macular dystrophies are marked by the accumulation of lipofuscin (fluorescent deposits) in the retinal pigment epithelium (RPE) cell layer. In the aged human eye for example, lipofuscin can occupy as much as 20% of the volume of each RPE cell. Although this RPE layer is extremely thin (around 10 micrometer or 5-10 times thinner than the diameter of a human hair), it is critical for the proper functioning of the retina because it acts as a transport exchange system with the blood vessels and is critical for the regeneration of the photoreceptors.
The accumulation of lipofuscin in the RPE is believed to play an important role in the course of these diseases: lipofuscin levels increase and contribute to a decline in cell function, followed by vision loss.
Various in vitro experiments have demonstrated lipofuscin’s toxicity to RPE cells by a variety of mechanisms (example of oxidative stress on the figure). It has also been argued that lipofuscin acts as a nucleation site for "drusen". The number and appearance of drusen is used as a primary clinical sign for diagnosing and grading the severity of macular degeneration. Lipofuscin has also been implicated in stimulating inflammatory responses and inflammation has been suggested as an underlying cause of macular degeneration.
Others argue that there is sparse evidence that links lipofuscin accumulation with retinal degeneration. In fact, most clinical evidence is based on observation that lipofuscin is observed prior to retinal lesions. A formal cause-and-effect relationship between RPE lipofuscin and the development of retinal degeneration has not yet been clearly established. Moreover, decades after its discovery in the eye, it remains a mystery as to just how lipofuscin is exactly formed.
As the accumulation of lipofuscin is one of the earliest signs of aging, it has been theorized that methods to prevent its formation may even slow aging; developing a clinical method to stop, control or reduce the accumulation of ocular lipofuscin could lead to a critical therapeutic treatment for the prevention of vision loss.
In the disc lumen of the normal functioning eye a portion of the vitamin A derivative retinaldehyde is bound to a phosphatidylethanolamine lipid. A rim protein is responsible for transporting most of the retinaldehyde – phosphatidylethanolamine complex out of the disc lumen where retinaldehyde is then processed to enable vision. Patients with Stargardt’s disease have a genetic defect in the gene encoding for the rim protein, the ABCA4 gene. In the absence of its proper transporter, retinaldehyde – phosphatidylethanolamine complex reacts to form toxic vitamin A dimers (A2E and ATR-dimer), which precede clinical signs of Stargardt.
By protecting the chemical bond involved in the reactivity of the retinaldehyde – phosphatidylethanolamine complex to form vitamin A dimers, ALK-001 was able to slow the formation of A2E and lipofuscin. This protection can indeed allow more time for the retinaldehyde – phosphatidylethanolamine complex to be cleared out of the disc lumen via alternative pathways, preventing the formation of vitamin A dimers
ALK-001 is a compound resulting from several years of collaborative research across several scientific and medical fields. When placed in a test tube, ALK-001 slowed the reaction of formation of lipofuscin by 7 times (figure to the right). ALK-001 was then tested in an animal model of Stargardt disease and showed 80% reduction of A2E formation after 3 months and significantly better visual function as measured by electroretinogram (ERG) after 12 months (figure to the left).