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Shaping Up Proteins

Targeting misfolded proteins could usher in a brand new class of drugs.

In the mid-1990s, as the mad-cow-disease scare spread across Europe, scientists were beginning to accept a controversial idea: perhaps this contagious brain-wasting ailment was caused not by a virus or bacterium but by a protein already found in the body. Subtle changes in the shape of the normally benign protein could be enough to transform it into a deadly agent that turned the brains of cows and a few unlucky beef eaters into mush. Stranger still, researchers were beginning to find that other misshapen proteins were at the root of common ailments like Parkinson’s disease, Alzheimer’s disease, diabetes, and even cancer.

It was around this time that two of the leading scientists studying shape-shifting proteins – Susan Lindquist, then at the University of Chicago, and Jeffery Kelly of the Scripps Research Institute – began discussing the potential of drugs that prevent proteins from getting bent out of shape and unleashing their toxic effects. “I would say that within our first two conversations, we talked about starting up a company,” says Lindquist, who is now at MIT. And so was born the idea for FoldRx Pharmaceuticals. But the Cambridge, MA–based company didn’t actually get off the ground until December 2003, shortly before Lindquist left her post as director of MIT’s Whitehead Institute for Biomedical Research. Despite that lag, FoldRx is still one of only a few startups developing drugs that target misshapen – or misfolded, as researchers typically call them – proteins.

Having captured $16 million in first-round venture capital fi­nancing last December, FoldRx is now moving quickly. The firm has already made plans to start human testing later this year of a drug for a genetic disease called familial amyloid cardiomyopathy, which afflicts an estimated 150,000 Americans. It strikes when a misfolded blood protein accumulates in heart tissue, causing the heart to stif­fen and eventually fail. FoldRx’s experimental drug is de­signed to bind to the protein just after it is manufactured in the cell and prevent it from misfolding. The company hopes to take the drug all the way through the regu­latory approval process on its own, an expensive proposition for a small firm. A time-consuming one, too: the process typically takes at least seven years to complete.

With much of its ­resources devoted to developing drugs for familial amyloid cardiomyopathy, FoldRx may decide to partner with larger pharmaceutical companies for its other drug-development programs. Chief among them is an effort focused on Parkinson’s disease, which affects more than half a million Americans. Inside the brain of a Parkinson’s patient, researchers believe, misfolded proteins clump together, triggering the death of brain cells and causing the tremors associated with the disease. A drug that targets the protein “would be really amazing,” says Anne Young, a Harvard Medical School neu­rology professor and Parkinson’s-disease expert at Massachusetts General Hospital. “It could potentially stop the progression of Parkinson’s or slow it down a huge amount. It would be completely novel.” FoldRx hopes to start animal testing of promising drug candidates this year.

One major obstacle that the company could face as the Parkinson’s-disease project progresses is that it’s difficult to monitor protein clumping in the brain, says Chris Dobson, a chemistry professor at the University of Cambridge whose own startup, Zyentia, which is based in Cambridge, England, is also developing drugs for protein-misfolding diseases but does not yet have immediate plans to begin human tests. Such monitoring could be important in evaluating whether a ­potential drug is actually working. Researchers have recently begun developing imaging and diagnostic technologies that could do the trick, Dobson says, but the work is still in its early stages and will have to proceed quickly in order to give researchers at both startups the tools they need to test their new drugs in humans when the time comes.

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