Miami, FL (May 2007) — One of the keys to curing type 1 diabetes is to develop safe and effective methods to prevent the autoimmune reaction against the insulin-producing cells. While new drugs have been developed and are in use, they still cause unwanted side effects and are toxic to the organs, tissues and cells. These drugs also suppress the entire immune system, leaving patients at risk for infections and even cancer.
More recently, specifically-targeted agents, known as monoclonal antibodies, have been used to block the key immune system pathways that lead to transplant rejection. Over the last decade, the DRI has partnered with several pharmaceutical companies to test many of these agents for their ability to not only stop the autoimmune reaction against the islets but prevent rejection of transplanted tissue.
These drugs, however, are traditionally developed by pharmaceutical companies, and researchers must wait for new agents to become available for use. Additionally, the companies maintain control over whether a particular drug will be pursued for commercialization and if not, researchers are denied access to it despite any successful outcomes in the testing phase.
“At times, even when an agent has gone through discovery, development and market assessment stages, we have been subject to the inaccessibility of highly promising agents for our studies,” explains Dr. Norma Sue Kenyon, DRI associate director of research and program development and director of pre-clinical research, who has worked with many companies to develop and test new agents. “If any one thing could change the face of diabetes and transplantation, it would be the availability of specific, effective and safe immune intervention agents that are produced by DRI teams and readily available for our studies, free from market-driven pressures,” says Dr. Kenyon.
Buchwald to lead initiative
To address this issue, the Diabetes Research Institute has launched a major drug discovery initiative and appointed Peter Buchwald, Ph.D., as its director. Dr. Buchwald, who is also assistant professor in the Department of Molecular and Cellular Pharmacology at the University of Miami Miller School of Medicine, was previously a member of the New Drug Development department of IVAX Research, Inc., which became part of Teva Pharmaceuticals in 2005.
Dr. Buchwald’s expertise lies in many areas related to drug design and development, as well as in the regulatory issues involved in bringing new agents through the various phases of testing and, ultimately, to clinical application. As the inaugural director of the DRI’s Drug Discovery Program, Dr. Buchwald recognizes a significant opportunity for the DRI to generate its own arsenal of therapeutic agents.
“The general need for a diabetes-focused drug discovery project is well illustrated by the fact that whereas mortality rates for heart attacks, breast cancer and stroke have significantly decreased since the 1980s – mainly due to the introduction of new drugs and therapeutic methods – they increased for diabetes,” he said.
Through this initiative, which is comprised of two main strategies, the DRI plans to speed up the testing sequence of any promising, next-generation agents with the intent to make them available to patients as soon as possible.
Identifying small molecules
In the first approach, Dr. Buchwald and his team are identifying small molecules that can selectively target and block immune cell signals — which trigger the autoimmune reaction — when they are activated against islets or other transplanted tissue.
“By ‘small molecule’ we usually mean traditional pharmaceutics, such as drugs prepared by chemical synthesis with a [low] molecular weight. In contrast, newer biotechnology products, like antibodies, would be considered ‘large-molecule’,” he explained.
The premise is that small molecule drugs could eliminate the adverse side effects associated with current treatments that use relatively large molecules. In particular, the next-generation drugs would be used to target co-stimulatory pathways, such as CD40-CD154.
The DRI has already shown that blocking this pathway in nonhuman primates has provided the most effective and longest lasting immunomodulatory intervention to date.
Compared with other immune intervention agents typically available, this monoclonal antibody targeting this pathway successfully blocked transplant rejection and allowed for normalized blood sugars for more than five years. Using conventional therapy, islets would maintain function, on average, for only 10 days. Additionally, the new study agent was not toxic to tissues, organs or the islets themselves.
While DRI researchers did not observe any side effects or complications from this preclinical islet transplantation study, an increase in blood clots was seen in other clinical settings. As a result, the company that manufactures this drug halted its use and prevented further research. However, the CD40-CD154 pathway remains of critical importance for researchers and will be investigated and characterized for clinical use by the DRI’s new initiative.
Dr. Buchwald said, “The therapeutic targeting of such costimulatory pathways is a very important goal. These pathways are likely to be involved not only in inducing long-term transplantation tolerance, but also in the mechanism of autoimmune diseases themselves.
Using implanted device
The second strategy explores the possibility of delivering immunosuppressive drugs locally to an implanted device. Dr. Buchwald suspects that low-dose corticosteroids, a “soft drug,” may be especially good for local use, since it is specifically designed to deliver the desired therapy and then break down into a harmless substance. This in turn could eliminate many of the serious problems associated with current systemic therapies, such as inflammation and infections.
Drug discovery and development involves a truly multidisciplinary approach. It encompasses several areas of chemistry, physiology and pharmacology, as well as regulatory and clinical sciences, among others.
“I expect that the considerable multidisciplinary experience here at the DRI in combination with the knowledge I’m bringing from various fields will prove useful in the end,” he says. “This is an excellent fit with the collaborative philosophy embraced by the DRI.”
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Lori Weintraub, APR