June 2015
Volume 56, Issue 7
ARVO Annual Meeting Abstract  |   June 2015
Small Molecule Inhibition of Crystallin Protein Aggregation in Hereditary Cataracts
Author Affiliations & Notes
  • Leah Makley
    ViewPoint Therapeutics, San Francisco, CA
  • Usha Andley
    Ophthalmology and Visual Sciences, Washington University, St Louis, MO
  • Jason Gestwicki
    Institute for Neurodegenerative Diseases, University of California at San Francisco, San Francisco, CA
  • Footnotes
    Commercial Relationships Leah Makley, ViewPoint Therapeutics (E), ViewPoint Therapeutics (F); Usha Andley, ViewPoint Therapeutics (S); Jason Gestwicki, US 20140031327 (P), ViewPoint Therapeutics (C)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 3215. doi:
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      Leah Makley, Usha Andley, Jason Gestwicki; Small Molecule Inhibition of Crystallin Protein Aggregation in Hereditary Cataracts. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3215.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: The molecular chaperone αB-crystallin is a major structural protein in the ocular lens. The mutation R120G promotes its misfolding and aggregation, resulting in hereditary, early-onset cataracts. We tested the hypothesis that R120G αB-crystallin ligands could prevent or reverse its aggregation, using in vitro studies with recombinant protein and R120G αB-crystallin knock-in mice.

Methods: We conducted a high-throughput screen to identify a class of small molecules that directly bind to R120G αB-crystallin. The binding interaction was verified using biolayer interferometry and nuclear magnetic resonance, and the structure-activity relationships were characterized. The anti-aggregation properties of an optimized compound were characterized by electron microscopy and light scattering assays using recombinant protein. To assess the effects on lens transparency, an eyedrop solution of the lead compound or a vehicle-only control was administered to R120G αB-crystallin knock-in mice for two or four weeks. Slit lamp biomicroscopy was used to qualitatively assess lens transparency, and complemented by measurements of lens protein solubility.

Results: In heterozygous R120G cryAB +/- mice, 28 of 33 mice (85%) exhibited improved lens transparency, while 7 of 9 (78%) of homozygous R120G cryAB -/- mice were improved. Conversely, a negative control molecule had no effect on lens transparency in three R120G cryAB -/- animals. The solubility of α-crystallins increased by 63% in the treated relative to the vehicle-only control eyes, and total lens protein solubility increased by 16 ± 5% (n=7).

Conclusions: Topical administration via eyedrop was found to reverse crystallin protein aggregation and correct lens transparency in the R120G αB-crystallin genetic model of cataract. These observations suggest a potential pharmacological treatment modality. Ongoing work will continue to evaluate the efficacy, pharmacokinetics, safety, and mechanism of action of the intervention.


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