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Nov 12, 2015
 |  BC Innovations  |  Product R&D

Crystallin-clear ViewPoint

ViewPoint Therapeutics targets biophysical interactions in cataract and beyond

By exploring the biophysics of proteins with disease-associated mutations, a UCSF group has developed a way to screen for drugs that rescue the activity of non-enzymatic targets, and proved its value with molecular chaperones. After finding a compound that clears up cataracts, the team formed ViewPoint Therapeutics Inc. to commercialize its approach under the wing of JLABS, Johnson & Johnson's network of life sciences incubators.

The cataract study, published last week in Science, is the first application of what ViewPoint hopes will be a widely applicable strategy for targeting disease-associated mutations whose phenotypic effects are unclear. Leah Makley, CSO of ViewPoint and first author on the study, thinks the broad biophysical approach will open the doors to targets about which there is little information.

"In the post-genomic era, the field has identified new classes of protein targets that have been implicated in disease through genetic screens, but we have a poor understanding of the structure and function of many of these new targets," she said.

Makley began the study by seeking an approach to target non-enzymatic molecules like molecular chaperones, whose lack of catalytic readout had made high throughput screening strategies elusive. "I was particularly interested in looking at protein targets that were labeled undruggable," she said.

The study began in 2011 at the University of Michigan under principal investigator Jason Gestwicki, who transferred to University of California San Francisco in 2013 and founded ViewPoint in 2014. He told BioCentury that α-crystallin heat shock proteins, whose misfolding promotes cataracts, fit the "undruggable" criterion. The only treatment for cataracts is surgery.

"For the α-crystallins, it's not immediately obvious what differentiates the diseased form from the normal form. Leah's big accomplishment was to realize that the stability of the diseased form, which is an amyloid, is much greater than the normal form," said Gestwicki.

That led the team to focus on molecules that could promote the normal dimer formation by CRYAB - a key α-crystallin in the human lens - and thereby prevent mutant proteins from forming the highly thermodynamically stable aggregates that cloud vision.

"What we did was develop a way to screen for molecules that could take the abnormal behavior of a mutant protein and rescue that phenotype to make it look like the wild-type protein," Makley told BioCentury.

In its Science paper, the team published data showing the screening system yielded what is now one of ViewPoint's lead compounds, an endogenous metabolite in the cholesterol biosynthetic pathway.

In July, a study in Nature led by the University of California San Diego's Kang Zhang found human genetic deficiencies in the...

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