We have devised a novel biophysical method to identify molecules that can interact with misfolded proteins and promote their native, functional shape. Our method leverages the idea that heat can be used to measure the stability of crystallin proteins. With this new method, we identified VP1-001: a molecule that effectively stabilizes the soluble native form of alpha-crystallin to reduce misfolding and aggregation, and consequently prevent and counteract lens disorders such as cataracts and presbyopia.
We plan to build on our promising preclinical results with VP1-001 and prepare for initial human clinical studies in patients with cataracts that are poorly addressed with conventional surgery. In parallel, we are developing new and improved molecules targeting crystallins and beginning to apply our platform screening technology to other (undisclosed) misfolded protein targets both inside and outside of ophthalmology.
+ What are crystallins?
Crystallins (alpha-, beta-, and gamma-) are the fibrous proteins that form the majority of the structure of the eye’s natural lens. In their native, properly-folded state, crystallins grant the lens its transparency, refractive index, and flexibility. Crystallins are mostly expressed in the lens early in the eye’s development. Once these proteins are synthesized, they do not turn over – they are some of the longest-maintained proteins in the human body. Their long lifetime makes them vulnerable to the accumulation of accidental chemical modifications that can ultimately destabilize the proteins’ structure, compromise their function, and result in aggregation. When these proteins aggregate, they lose their orderly arrangement in the lens, leading to lens stiffening (presbyopia) and light scattering (lens opacity, or cataract).
+ What are alpha-crystallins?
Alpha-crystallins constitute 30 percent of the protein content of the lens. They are molecular chaperones that help maintain the solubility of beta- and gamma- crystallin, and therefore are a key target for preventing and reducing total crystallin aggregation in the lens.