Abstract
Purpose :
Dysfunctional lens syndrome (DLS) is a progressive disorder of lens protein aggregation in which the crystalline lens gradually becomes less flexible and opaque with age. This manifests clinically in humans as presbyopia in the 40s and cataract in later life. The crystallins (α, β, and γ) are the most abundant lens proteins. The α-crystallins act as chaperones for the β and γ-crystallins, keeping them in their native soluble confirmation and preventing them from aggregating. We have demonstrated the efficacy of 25-Hydroxycholesterol (25-HC) in reversing lens opalescence in non-human primates with spontaneous cataracts. However, 25-HC is a poor drug candidate due to: limited aqueous solubility (<1 uM), poor lens bioavailability, and retinal toxicity (1). Visus is developing next-generation α-crystallin chaperones with improved physicochemical properties, potency, pharmacokinetics, and tolerability.
Methods :
Approximately 300 non-oxysterol compounds have been synthesized and characterized. Epithelial permeability was measured in Madin-Darby canine kidney (MDCK) cells. In vitro potency was determined by evaluation of the ability to prevent aggregation of a mutant crystallin (R120G cryAB) that is known to cause human hereditary cataracts in vivo (2). Ocular tolerability of a development candidate VIS-001052 was evaluated after a single intravitreal injection of a saturated solution of VIS-001052 in Dutch Belted (DB) Rabbits over a 7-day period using the Hackett-McDonald ocular scoring system.
Results :
VIS-001052 exhibits much improved aqueous solubility over 25-HC (100 - 500 ug/mL vs <1 ug/mL) with good epithelial permeability (Papp = 10.9 x 10-6 cm/s) and ~10-fold greater potency than 25-HC (1 µM vs 10 µM). VIS-001052 was well-tolerated over 7 days after a single intravitreal injection in DB rabbits.
Conclusions :
Next-generation α-crystallin chaperones have demonstrated much improved solubility and potency over 25-HC and are well-tolerated following a single intravitreal injection. VIS-001052 represents a promising candidate for further development in DLS.
1. Br J Pharmacol. 2021;178:3205–3219
2. PLoS One. 2021 Sep 14;16(9):e0257098
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.