Lipofuscin bis-retinoid (LBR)

Lipofuscin bis-retinoids are a group of fluorescent pigments, most notably A2E (N-retinylidene-N-retinylethanolamine), that accumulate within the lysosomes of retinal pigment epithelial (RPE) cells as a byproduct of the visual cycle (Sparrow et al., 2012). These compounds form through the non-enzymatic reaction of all-trans-retinal with phosphatidylethanolamine in the photoreceptor outer segments before being phagocytosed by the RPE (Radu et al., 2003). Their accumulation is a primary driver of retinal degeneration, as they exhibit potent detergent-like properties that destabilize lysosomal membranes and act as photosensitizers that generate reactive oxygen species upon blue light exposure (Sparrow et al., 2010). In diseases such as Stargardt disease and age-related macular degeneration (AMD), the excessive buildup of these bis-retinoids leads to RPE atrophy and subsequent loss of photoreceptors (Charbel Issa et al., 2013). Therapeutic interventions aim to limit the formation of these compounds by inhibiting key enzymes in the visual cycle, such as RPE65, or by reducing the systemic transport of vitamin A to the eye via RBP4 antagonism (Kubota et al., 2014; Mata et al., 2021). Additionally, novel approaches like the use of deuterated vitamin A (ALK-001) seek to slow the chemical dimerization process that creates these toxic byproducts (Charbel Issa et al., 2015).

Other names

A2EN-retinylidene-N-retinylethanolamineOcular lipofuscinBis-retinoid fluorophoreall-trans-retinal dimerRetinal pigment epithelium lipofuscin

Reduction of bis-retinoid formation through visual cycle modulation (RPE65 inhibition), reduction of vitamin A uptake (RBP4 antagonism), or slowing of chemical dimerization (C20-deuteration of vitamin A).