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May 11, 2006

New institute seeks cures for orphan diseases

Orphan disease research has found a new home at Pitt.

Experts in chemistry, pharmacology and biology are joining forces in a new lab in their quest to cure rare diseases. Using new rapid screening methods, they plan to test thousands of chemical compounds each year to find which ones show promise as potential medications.

Once compounds are identified, researchers at Pitt’s new Drug Discovery Institute (DDI) hope to quickly develop them into medicines that will find their way into the hands of a person in need of a cure where once there was none.

The work is urgent because rare diseases, unfortunately, are not so rare. According to the National Institutes of Health (NIH), an estimated 25 million people in the United States have a rare disease — defined as a condition that affects fewer than 200,000 people in this country. The NIH Office of Rare Diseases, which coordinates research on these illnesses, labels more than 6,000 rare conditions as so-called orphan diseases. These diseases are largely ignored by for-profit drug firms because they are not commercially viable pursuits, given the high development costs, said DDI co-director John Lazo of pharmacology. The list of such “orphans” is likely to grow, Lazo said, as researchers increase knowledge of the underlying causes of disease.

DDI researchers from around the University began settling into their space on the 10th floor of the new Biomedical Science Tower 3 this spring. By fall, when newly recruited researchers arrive and the full complement of 30-50 staff members is in place, DDI and the NIH-funded Molecular Libraries Screening Center within it will be prepared to quickly analyze chemical compounds to determine which show promise as potential medications. The screening center, with an extensive chemical library and rapid methods for pinpointing which have the right characteristics to warrant a closer look, has multiplied researchers’ ability to move forward toward finding cures and developing medications more rapidly.

The goal, said Lazo, is to screen 100,000 compounds for each disease target every week. “A decade ago, if I looked at 10 compounds per year, I was really proud, “ Lazo said. “Five years ago if I looked at 5,000 per year, I was a big shot.”

DDI’s chemical library of perhaps a half-million compounds is like a refrigerator of sorts. Instead of milk, eggs and meat, this fridge contains representatives of various chemical families stored on plates at -20C in a unit the size of a small car, retrievable on request by a robotic arm.

Today’s automated screening methods put Lazo’s earlier numbers to shame, but raise another problem: The amount of data generated is enough to fill up a computer’s entire hard drive in a single day, he said.

DDI co-director Peter Wipf of chemistry said Pitt is not competing with pharmaceutical companies. He noted that academic institutions are better able to address the issue of orphan diseases. Unfettered by the same profit motive as commercial firms, universities can focus on the discovery component, perhaps leaving only the final steps in the process to the for-profits.

A 2003 study by consulting firm Bain & Co. estimated that the cost of developing a drug from discovery to commercialization is about $1.7 billion. The high investment compared to the low number of potential customers makes it unlikely that drug companies will pursue development of drugs that treat orphan diseases.

“Drug companies are interested in blockbusters,” Lazo said. Because of the high costs of development, there’s little incentive for pharmaceutical companies to search for medications that will have only a handful of buyers. “They want a sure bet. If they make a me-too version of a medicine for a common illness and get 10 percent of the market share, they can make a billion dollars,” he said.

Regardless, he said, there is a need to answer the question: “How as a society do we actually deal with the issue of drugs or small molecular substances that could be applied to diseases that have been ignored?”

And once a discovery is made, how is it turned into a final product that can help the handful of people who need it?

“We can get compounds to the point where some commercial organization will take them and run with them,” Lazo said. The discoveries could be licensed to an outside entity, or the University itself could spin off a company. Even certain foundations that serve sufferers of specific diseases might be interested, he said.

By placing the discovery research and testing in the academic realm rather than the for-profit sector, “We can reduce the [economic] risks of bringing drugs to the market,” Lazo said.

The drug development process is lengthy. Once a compound is screened and found to have characteristics that could be useful in treating a particular disease or condition, fine-tuning to discover the most favorable attributes comes next. Researchers look for the compound that has the proper potency, fewest side effects, or is most effective from a family of similar compounds. Once tested in an animal model, the process turns toward making the compound more “drug-like.” It’s important to find a form that will not break down too rapidly or remain too long in one’s body, and to manipulate it so that it can be taken in a patient-friendly way, such as one pill per day, Lazo said.

The timeline from discovery to final commercialization can take about a decade, although medications that are deemed by the Food and Drug Administration to cover unmet medical needs — such as those for orphan diseases — may be fast-tracked.

Selecting targets is a multi-faceted process. “It is a complex process of deciding and ranking them,” Lazo said. Among the criteria would be whether someone on campus has an interest or is working on research in a particular disease, Lazo said. Or, there may be a particular compound that piques the interest of Pitt’s chemists.

And, “Some targets are neater than others,” Lazo said. “If there’s some disease influenced by or caused by an enzyme that an individual is interested in, we may turn our attention there.”

In addition, some foundations and organizations may choose to sponsor some of the institute’s work if they perceive a lack of study exists for a particular disease.

Initially, DDI will focus on five diseases a year, Lazo said.

Among the possibilities on the list would be drugs for cancers, most of which, he said, are orphan diseases. In addition, some collaboration with Pitt researchers who study neurogenerative diseases is planned. And, there is an interest in finding drugs that prevent protein-protein interactions in cells such as occurs in systemic amyloidosis or in the amyloid plaques that characterize Alzheimer’s disease.

“We’re not going around with a solution in hand looking for a problem,” Wipf said, noting that chemists are problem solvers.

“The process is application driven. We look for a disease state where there’s no effective treatment, then try to develop the chemistry, biology and pharmacology to address those needs.”

Wipf said a three-dimensional approach to such complex research is crucial. Collaboration adds the dimension of critical evaluation from specialists in other disciplines, an advantage over more traditional research that can permit a researcher to “follow one line way too long,” Wipf said.

The academic pursuit is one Lazo said Pitt is well equipped to handle. “One huge advantage of the University of Pittsburgh that’s sometimes overlooked by the people who are here is that the School of Medicine is right next to Arts and Sciences, is right next to the School of Pharmacy,” he said. “We have a unique combination of disciplines that can complement each other in this research.”

Wipf said that although there has been no overarching University vision to join all drug development efforts under one roof, DDI is a step forward toward three-dimensional research. “We’re looking at one experiment in a big campus that’s mostly departmentally based,” Wipf said. “Shared facilities not based on departmental variation is a step in the right direction.”

He is optimistic about the potential for finding cures, saying something tangible could be discovered soon. He already has materials he’s anxious to analyze.

“The needs of people who have a rare disease are severely disregarded,” Wipf said. “This is an incredible opportunity and a challenge.”

—Kimberly Barlow

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