Indy Startup 'Cracks the Code' in Enzyme Research

Tuberculosis (TB) is not of great concern for most Americans—the Centers for Disease Control and Prevention (CDC) reports TB reached an all-time low in the U.S. in 2009. However, the disease is of grave concern worldwide; CDC data shows one-third of the world's population is infected with the difficult to treat disease. Leaders of Indianapolis-based startup Aarden Pharmaceuticals believe they've "cracked the code" for more effectively treating TB—potentially sparking a chain of treatments for various diseases that extends as far as cancer.

Aarden's technology is based on a group of enzymes called protein tyrosine phosphatases (PTPs), a 100-member family of enzymes in the human body. Aarden Co-founder Dr. Zhong-Yin Zhang says the enzymes play a key role in a long list of diseases, including cancer, diabetes and rheumatoid arthritis, but the company will initially focus on TB.

Zhang's chemistry breakthroughs could improve drugs' effectiveness by more precisely finding their target. Zhang says the company is starting with TB because the bacterium is a relatively easy target, and the world is in great need of improvements for treatment; there are 2 million TB-related deaths globally each year, with most in India, China, Africa and the former Soviet Union.

"There's a cure for TB, but it requires four to five cocktails of antibiotic for six to nine months," says Zhang, who is also Robert A. Harris Professor and Chairman of Biochemistry and Molecular Biology at the Indiana University School of Medicine (IUSM). "There's very poor compliance from patients; very few people take it all the way through, and if you stop, that causes drug resistance. The drug resistant cases are even harder to treat."

Additionally, the antibiotic cocktails are far from modern; Zhang says the drugs were discovered about 50 years ago. Government organizations and nonprofits such as the AIDS Healthcare Foundation are clamoring for a better treatment, as TB is a leading killer of HIV-infected people.

Aarden President and Chief Executive Officer Gary Noonan says TB is so difficult to treat because the bacteria "turn off" cells' natural protective responses.

"Our approach is entirely different than other approaches. Most approaches to treat TB are antibiotics; they directly attack the TB bacterium and try to kill it," says Noonan. "However, our drug allows the cell to do what it's normally supposed to do to protect itself. That ability should then result in a drug that would be complementary to other existing—and potentially—new TB compounds. Our hope is this drug, in combination or by itself, would speed up the recovery or the amount of time that an infection lasts." Listen

Zhang believes the PTP field of research has yet to produce a drug because the staggering number of enzymes—over 100 in the PTP family—makes it difficult to create a drug with selectivity. He says the pharmaceutical industry has historically regarded the PTP family as "undruggable," and therefore, has not invested in the area of research. Listen

"We've generated a very exciting technology that enables us to address specificity—we want to specifically attack the disease-causing target," says Zhang. "We chose TB for proof of concept; developing a drug against this TB target is a good indication that we can also target other diseases, such as cancer and autoimmune diseases." Listen

Aarden leaders believe a successful TB treatment will, like a domino effect, help them develop treatments for diseases such as leukemia, lung and breast cancer and lupus, which also involve the same family of PTPs. Noonan says the biggest challenge moving forward will be to attract critical funding to advance the technology.

"This 'Valley of Death' [for drug research] is really a true thing," says Noonan. "You're in a 'catch 22' for a period of time where people want to see more data, but you can't get the money to advance the research and provide more data. I think Indiana has played a role in helping us move the technology forward to a point where we're able to get bigger investors with deeper pockets." Listen

Noonan says funding from a handful of Indiana sources, including the 21st Century Research and Technology Fund and BioCrossroads, was also vital in positioning the company to attract investors on a "national scale."

Aarden is now focused on advancing its research in all three areas—TB, oncology and autoimmune diseases—and expects definitive results in its TB platform by the end of the summer, helping prepare it for an IND (Investigational New Drug) application by the first quarter of 2012. It's an important milestone for Zhang, a scientist anxious to see his 30 years of research make an imprint on the world.

"It's exciting to see a technology we've developed here at IUSM have a chance to see some commercial future," says Zhang, "Ultimately, it will benefit patients."

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