# Modulation of Lipid Bisretinoids Clearance with Beta-Cyclodextrins

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $490,029

## Abstract

PROJECT SUMMARY
 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 (βCDs), 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). βCDs 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 α-synuclein (α-
syn) in Parkinson and amyloid-β in Alzheimer Disease. In NPC cells, clearance of FC
depends on βCDs' ability to form complex with FC. In contrast, their ability to clear
ceroid lipofuscin and α-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, βCDs 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 βCDs for LB-induced
retinal disease. Furthermore, to maximize the safety, potency and retinal biodistribution
we propose to optimize nanoparticles (βCD-threaded polyrotaxanes) that have already
shown effective βCD delivery into LY of NPC cells. Finally, we will test the efficacy of
βCD-based approaches alone or in combination with TFEB-based strategies in
ABCA4RDH8-/- mice, an animal model of LB-driven retinal degeneration. Because β-
CDs are FDA approved, success in this proposal could be quickly extended into clinical
trials in humans.

## Key facts

- **NIH application ID:** 9882275
- **Project number:** 5R01EY027422-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** MARCELO M NOCIARI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $490,029
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882275

## Citation

> US National Institutes of Health, RePORTER application 9882275, Modulation of Lipid Bisretinoids Clearance with Beta-Cyclodextrins (5R01EY027422-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9882275. Licensed CC0.

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