Beta Cyclodextrins as a Possible Treatment for the Build Up of Lipofuscin
Liposfucin is the name given to a mix of hardy metabolic waste compounds that build up in long-lived cells over the years, such as the vital cell populations of the retina. Cells are not equipped with suitable tools to remove this gunk, but they try anyway and so it ends up concentrated in the cellular recycling structures known as lysosomes. This leads to bloated, poorly functional lysosomes and a decline in cellular housekeeping, which in turn causes cell dysfunction and loss of tissue function. In the retina this process contributes meaningfully to a number of progressive blindness conditions such as age-related macular degeneration.
Here researchers report on a possible drug candidate that renders harmless some fraction of a few of the important lipofuscin constituent compounds when used on retinal cells:
Lipofuscin accumulation in the retinal pigment epithelium (RPE) is a hallmark of aging. Accumulation of lipofuscin bisretinoids (LBs) in the RPE is the alleged cause of retinal degeneration in genetic blinding diseases (e.g., Stargardt) and a possible etiological agent for age-related macular degeneration. Currently, there is no treatment to prevent and/or revert lipofuscin-driven retinal degenerative changes. Hence agents that efficiently remove LBs from RPE would be valuable therapeutic candidates.In this study, we report that beta cyclodextrins (β-CDs), cyclic sugars composed of seven glucose units, can bind retinal lipofuscin, prevent its oxidation and remove it from RPE. Computer modeling and biochemical data are consistent with the encapsulation of the retinoid arms of lipofuscin bisretinoids (LBs) within the hydrophobic cavity of β-CD. Importantly, β-CD treatment reduced by 73% and 48% the LB content of RPE cell cultures and of eyecups obtained from [mice], respectively. Furthermore, intravitreal administration of β-CDs reduced significantly the content of bisretinoids in the RPE of [mice].
Thus, our results demonstrate the effectiveness of β-CDs to complex and remove LB deposits from RPE cells and provide crucial data to develop novel prophylactic approaches for retinal disorders elicited by LBs. This study opens an avenue to develop small drugs against, currently untreatable lipofuscin-associated blinding disorders.