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May 15, 2013 (Vol. 33, No. 10)

Seasoned Drugs Offer Therapeutic Gold Mine

  • The process of discovering new drugs is mainly linear—and prone to bottlenecks. Putting a new drug on the pharmacy shelf may take well over a decade, which spells a waste of time and money if the drug fails once it reaches the market.

    Drug repositioning (or repurposing), however, promises to be faster and cheaper. In drug repositioning, researchers search already-approved drugs to see if they might have a hitherto unforeseen effectiveness against particular diseases (unrelated to the conditions against which they were originally developed).

    Because the approved drugs have already been tested in humans, repositioning a drug saves time. Important information such as toxicity, pharmacology, and dosage details, for example, have already been gathered. Many repositioned drugs can move straight into Phase II trials, and can thus meet the needs of patients sooner, and with lower costs.

    Drug repositioning can result in researchers learning more about a drug’s mechanisms of action, or the biology of the pathway it affects—and sometimes leads to new and more promising drug compounds. Today, scientists are pursuing various types of drug repositioning.

  • Click Image To Enlarge +
    University of Chicago scientists have uncovered the basic principles of cross-talk between pathways. This image was produced from reverse engineering significant molecular pathways associated to protein domains and molecular functions of their constituent molecules. A few pathways and their associations are shown in orange. Each point on the circle corresponds to a distinct entity.

    Computational biology is key to the repositioning methods used by Yves Lussier, M.D., professor of medicine and engineering, and director of the Institute for Interventional Health Informatics at the University of Illinois at Chicago. Dr. Lussier and colleagues use “hypothesis-anchored computational biology” to study drug repositioning, which begins with making hypotheses about how a repositioning might work.

    “We use network-based repositioning to find aberrant re-entry mechanisms, which is conceptually different from pathway-based,” he says. For example, for interacting proteins, they would examine the literature for known published interactions, knowledge bases such as KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology project), and results from yeast-2-hybrid studies. Alternatively, they may use genome-wide repositioning with GSEA (Gene Set Enrichment Analysis).

    Dr. Lussier suggests that there is room to grow in this field of research. Despite the available funding, he says that a limited number of researchers have the experience and skills required not only to apply computational biology to drug repositioning, but also to interpret the biological context and see the drugs through clinical trials. “The biggest challenge is to empower the right groups and establish the most cost-efficient approaches to reposition drugs,” he says.

  • Click Image To Enlarge +
    Using existing drugs in new ways to probe biological function can increase our ability to understand disease. [Biovista]

    Researchers at Biovista are also using impressive computational power for drug repositioning. Their Clinical Outcome Search Space™ (COSS) technology ranks how relevant clinical outcomes (more than 29,000 of them) might be against all drugs, and against all human molecular targets. It can also analyze the relevance of all drugs against diseases of interest.

    “COSS combines experimentally derived data about on- and off-target pharmacology with data from multiple sources about every drug, every indication, and every adverse effect, to generate unique data profiles for every drug, disease, adverse event, or human molecular target,” says Biovista’s president, Aris Persidis, Ph.D. “COSS then compares and ranks the data profiles to determine the most relevant ones, which are then validated experimentally.”

    Biovista has already repositioned two drugs for the progressive form of multiple sclerosis (MS), which has had few treatment options. Most MS drugs, for treatment of the relapsing-remitting form of MS, compromise the patients’ immune systems and have significant side effects. Biovista wanted to find non-immunomodulatory drugs that would treat the neurodegeneration that occurs in the progressive form of MS.

    COSS found an unknown role of mitochondrial dysfunction in MS, which previously had been thought a purely autoimmune disease. Therefore they used COSS to reposition drugs against mitochondrial—rather than autoimmune—dysfunction, resulting in two drug candidates (BVA-101 and BVA-201) that they then validated as effective in animal models of MS.

    “COSS was thus able to help redefine the potential mechanism of the disease, opening up fresh new opportunities for unanticipated therapies,” says Dr. Persidis. “Biovista is currently designing first-in-human studies for its MS program candidates.”

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