Abstract
Purpose :
We previously reported that a single intravitreal (IVT) administration of 25-hydroxycholesterol (25-HC) resulted in clinically meaningful reductions in lens opacity in age-related cataract in primates (1). However, due to poor tolerability, physicochemical properties, and stability, the compounds were not developable. This next generation of αCC (Gen 2) improves the potency, stability, lens pharmacokinetics and tolerability.
Methods :
The chemical and metabolic stability of the compounds were determined in isotonic phosphate buffer and isolated porcine vitreous humor (VH) spiked with 100 µM of αCC. In vitro potency was determined in an R120G αC aggregation assay. Ex-vivo porcine and human lens uptake and retention was determined in lens incubation studies. Tolerability and lens PK was also assessed in rabbits after intravitreal administration. Preservation and restoration of porcine and human lens clarity was determined ex-vivo in lens incubation studies. Dynamic light scattering, measured as a lens crystallin index (2), was used to quantify crystallin aggregation in the lens over time.
Results :
The aqueous half-life of the scaffold was improved from hours to years based on accelerated data and it does not significantly degrade in the VH over 24 hours. The potency of the lead candidates improved up to 100-fold over 25-HC. The Gen 2 scaffold was well-tolerated in rabbits and IVT injection with a 3% suspension achieved lens nucleus levels over 200-fold greater than the IC50 and up to 50-fold higher than lens levels achieved with 3% IVT 25-HC. Target engagement resulted in an accumulation of the chaperone in the lens and slow, prolonged clearance from lenses ex-vivo. A significant improvement in treated human and porcine lens clarity was observed over vehicle controls, and a marked decrease in porcine lens protein aggregation vs control was observed correlating with lens clarity. Reducing agent- αC chaperone co-drugs demonstrated cleavage back to the parent drugs in the vitreous with the chaperone retaining full potency.
Conclusions :
The increased potency, solubility, and bioavailability along with slow clearance of these candidates makes a neat injection or short-term sustained release implants potentially viable dosage forms for long term efficacy.
1. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2466
2. Trans. Vis. Sci. Tech. 2019;8(6):14
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.