Failure of Oxysterols Such as Lanosterol to Restore Lens Clarity from Cataracts

Abstract

The paradigm that cataracts are irreversible and that vision from cataracts can only be restored through surgery has recently been challenged by reports that oxysterols such as lanosterol and 25-hydroxycholesterol can restore vision by binding to αB-crystallin chaperone protein to dissolve or disaggregate lenticular opacities. To confirm this premise, in vitro rat lens studies along with human lens protein solubilization studies were conducted. Cataracts were induced in viable rat lenses cultured for 48 hours in TC-199 bicarbonate media through physical trauma, 10 mM ouabain as Na+/K+ ATPase ion transport inhibitor, or 1 mM of an experimental compound that induces water influx into the lens. Subsequent 48-hour incubation with 15 mM of lanosterol liposomes failed to either reverse these lens opacities or prevent the further progression of cataracts to the nuclear stage. Similarly, 3-day incubation of 47-year old human lenses in media containing 0.20 mM lanosterol or 60-year-old human lenses in 0.25 and 0.50 mM 25-hydroxycholesterol failed to increase the levels of soluble lens proteins or decrease the levels of insoluble lens proteins. These binding studies were followed up with in silico binding studies of lanosterol, 25-hydroxycholesterol, and ATP as a control to two wild type ( 2WJ7 and 2KLR ) and one R120G mutant ( 2Y1Z ) αB-crystallins using standard MOE TM (Molecular Operating Environment) and Schrödinger’s Maestro software. Results confirmed that compared to ATP, both oxysterols failed to reach the acceptable threshold binding scores for good predictive binding to the αB-crystallins. In summary, all three studies failed to provide evidence that lanosterol or 25-hydroxycholesterol have either anti-cataractogenic activity or bind aggregated lens protein to dissolve cataracts.

The Intravitreal Injection of Lanosterol Nanoparticles Rescues Lens Structure Collapse at an Early Stage in Shumiya Cataract Rats

“…In contrast to the results of Zhao et al [3], Daszynski et al failed to find evidence that lanosterol has either anti-cataractogenic activity or binds aggregated lens proteins to dissolve cataracts [4]. Taken together, it was suggested that the difference in the severity and part (cortex and nucleus) of the lens opacification may explain the contradiction in the previous reports for therapeutic effect by lanosterol [3][4][5], and our study may reflect both of these studies' results. Further studies are needed to elucidate the relationships between the effects of repair and structural collapse by lanosterol and to evaluate whether the application of lanosterol can return opaque lenses to transparency.…”

“…This discrepancy may be caused by the differences in the models, since the structural changes in the lenses of the dogs and rabbits used by Zhao et al were mild in comparison with those of the SCR-C [3]. In contrast to the results of Zhao et al [3], Daszynski et al failed to find evidence that lanosterol has either anti-cataractogenic activity or binds aggregated lens proteins to dissolve cataracts [4]. Taken together, it was suggested that the difference in the severity and part (cortex and nucleus) of the lens opacification may explain the contradiction in the previous reports for therapeutic effect by lanosterol [3][4][5], and our study may reflect both of these studies' results.…”

“…Lanosterol has been discovered in human genetics studies to solubilize crystallin aggregates in vitro and in cells and is also able to restore lens transparency in rabbits and dogs with age-related cataracts [3]. However, a recent report showed that culturing 25 mM lanosterol (approximately 1%) with lens nuclei from 40 age-related cataractous human lenses for 6 days at room temperature failed to dissolve the aggregated proteins or restore clarity to the lens nuclei [4,5]. Thus, it is unclear if lanosterol ameliorates lens clarity by increasing the ability to physically dissolve protein aggregates and/or the denatured amyloid-like fibril proteins present in cataractous lenses.…”

Inherited cataracts: molecular genetics, clinical features, disease mechanisms and novel therapeutic approaches

“…79 80 although recent studies have cast doubt on the efficacy of the identified oxysterols lanosterol and 25-hydroxy cholesterol to treat cataract. 81 The chemical chaperone 4-phenylbutyrate was used in mouse lenses to improve lens function in the genetic model of a cataract-causing connexin mutation (Cx50D47A) with limited success. 82 The search for small molecule inhibitors has been a consistent research goal over the decades with promising effects obtained with molecules such as pantethine, 83 rosmarinic acid and polyherbal preparations 84 and multifunctional antioxidants.…”

Molecular Processes Implicated in Human Age-Related Nuclear Cataract

“…The potential of such molecules to provide a nonsurgical treatment for cataract received a setback when detailed investigations failed to provide evidence that lanosterol or 25-hydroxycholesterol have anticataractogenic activity or bind aggregated lens proteins to clarify cataracts. 120 It is probably not possible to intervene in the spontaneous racemization, deamidation, or truncation events that characterize aged lens proteins since these appear to be driven primarily by heat and time. 16 On the other hand, it may be feasible to reduce protein-protein crosslinking since the dominant reaction involves nucleophilic addition of Lys or Cys residues.…”