Accumulation of toxic lipid bisretinoids (LBs) in lysosomes (LY) of retinal pigment epithelium (RPE) is a main etiological agent for recessive Stargardt disease (STGD1) and ABCA4-related forms of cone-rod dystrophy (CRD) and retinitis pigmentosa (RP). Furthermore, accumulation of LBs with age is a suspected risk factor for Age-Related Macular Degeneration (AMD). Hence, agents that remove LBs from RPE fulfill an unmet medical need for STGD1, CRD, RP and may help validate LBs as pharmacological targets in AMD. We have recently identified beta cyclodextrins (?CDs), cyclic sugars formed by 7 glucose residues, as promising bioactive compounds capable of removing LB from RPE cultures, from enucleated eyecups obtained from ABCA4/RDH8 double knock out (DKO) mice (a mouse model for accelerated LB deposition) and from DKO mouse eyes after intravitreal (IVT) injection (Nociari et al. PNAS, 2014). ?CDs are known for their ability to solubilize free cholesterol (FC) from biological membranes and to clear aberrant storage materials in lysosomal storage disorders, including FC in Niemann-Pick C (NPC), ceroid lipofuscin in Batten Disease as well as ?-synuclein (?- syn) in Parkinson and amyloid-? in Alzheimer Disease. In NPC cells, clearance of FC depends on ?CDs' ability to form complex with FC. In contrast, their ability to clear ceroid lipofuscin and ?-syn, depends on their capacity to modulate transcription factor EB (TFEB), a master regulator of LY, peroxisomal and mitochondrial function and of autophagy. As with FC, ?CDs form soluble complexes with LBs; however, the underlying clearance mechanism is unknown. Elucidation of the mechanism mediating LB clearance from RPE will facilitate the therapeutic utilization of ?CDs for LB-induced retinal disease. Furthermore, to maximize the safety, potency and retinal biodistribution we propose to optimize nanoparticles (?CD-threaded polyrotaxanes) that have already shown effective ?CD delivery into LY of NPC cells. Finally, we will test the efficacy of ?CD-based approaches alone or in combination with TFEB-based strategies in ABCA4RDH8-/- mice, an animal model of LB-driven retinal degeneration. Because ?- CDs are FDA approved, success in this proposal could be quickly extended into clinical trials in humans.

Public Health Relevance

Accumulation of toxic lipid bisretinoids (LBs) in lysosomes of retinal pigment epithelium (RPE) causes secondary death of photoreceptors (light sensing cells) in recessive Stargardt disease, certain forms of cone-rod dystrophy and retinitis pigmentosa and is a suspected risk factor for Age-Related Macular Degeneration (AMD). We have identified a family of cyclic bioactive compounds that dissolve and remove LBs from the RPE. Here we propose experiments to develop this seminal observation into a therapy against LB-driven retinal diseases.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Neuhold, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Schools of Medicine
New York
United States
Zip Code