Making Intelligent Therapeutics

By Jeff Norris

Mary Anne Koda-Kimble

UCSF School of Pharmacy Dean Mary Anne Koda-Kimble, PharmD, and leading scientists from the top-ranked pharmacy school spoke on June 23 about how their research is contributing to the development of better drug treatments.

The noontime luncheon presentation was hosted by the UCSF School of Pharmacy and the UCSF Office of Gift & Endowment Planning. The audience consisted of advisers to clients engaged in making gift decisions related to estate planning.

Koda-Kimble introduced the session by noting that drug side effects remain a significant challenge. “We have new drugs that manage disease and extend life spans, but there still are major problems.” Depending on the drug, risks may be serious, and may even include myocardial infarction, liver damage and susceptibility to bone fractures.

Challenges also remain in delivering drugs to the desired organ system and even to specific cell types. Preclinical studies in the laboratory and in animals are of limited value in gauging dosing, effectiveness, side effects and clearance.

In general, the current state of drug development is unsatisfactory and will change, according to Koda-Kimble, who is a pharmacist and is the co-author of the leading textbook on clinical pharmacy.

Among newly marketed drugs in 2006, “there were only 16 unique chemical entities,” Koda-Kimble noted, “even though billions are poured into this research. Something is not going right.”

Individuals clearly vary in their responses to drugs – in terms of both benefits and side effects – and genes play a role, Koda-Kimble asserted. Sometimes side effects do not become apparent until drugs already are on the market. In part, this may be because of lack of genetic diversity among clinical trial participants, she said.

For instance, Koda-Kimble says, there may be few individuals of Asian ancestry participating in a clinical trial. Yet often, “Asians do not metabolize drugs in the same way as Caucasians,” she notes. “Our vision is that we have a world in which every patient benefits from targeted therapies.”

Developing New Drugs

One key to continued UCSF contributions to the field is the recent creation of the Department of Bioengineering and Therapeutic Sciences, the first to marry bioengineering and pharmaceutical sciences, according to Koda-Kimble. Engineers, physicists and computational scientists are working with pharmaceutical scientists to come up with creative solutions to major challenges.

Sarah Nelson, Dr.rer.nat, co-chair of the new department, pointed out a few of the ways in which computational and engineering approaches are being applied to biopharmaceutical research.

Department research includes the development of smart pills that read signals from within and without the body and, in response, release drugs in a controlled manner, as well as development of artificial kidneys to replace dialysis, and imaging techniques that may allow for noninvasive monitoring of molecular biomarkers of disease. Nelson mentioned the possibility of one day being able to identify and quantify biochemical correlates of behavioral health, which could be a useful tool for evaluating drugs to treat depression, for instance.

Pharmacogenetics researcher Deanna Kroetz, PhD, described breast cancer research in which she and her colleagues are scanning all genes of early-stage breast cancer patients to identify genetic variations that may influence whether patients are likely to suffer harmful side effects from treatment. Any positive findings may find direct application in the clinic through the selection of drugs less likely to cause side effects for the individual patient.

Leslie Benet, PhD, has founded a company to commercialize his “man on a chip.” The tool promises to be an efficient and more accurate early screening technique for evaluating the efficacy and toxicity of new drug candidates.

With the use of microfluidic techniques, cells plated onto a plastic device are bathed in a liquid growth medium that acts like the blood supply in providing nutrients. Compared with other lab techniques, the device allows for a more realistic evaluation of the metabolism and elimination of pharmaceuticals. It also provides a way to gain new insight into how animal and human responses to particular drugs may be similar or different, Benet says.

Frank Szoka, PhD, explained how microscopic fat sacs called liposomes have been used as drug delivery devices. Szoka holds 26 patents related to new drug delivery techniques. He is the founder of a company that developed Doxil, a liposome-encapsulated version of doxorubicin, now used to treat breast cancer. He currently is working on new ways to better target treatment with new generations of liposomes. One project involves creating a vaccine to prevent HIV infection – one in which HIV proteins on the surface of liposomes would be exposed to prime the immune system.

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