NEW DRUGS AIMED AT T CELLS SUCCESSFULLY TREAT ARTHRITIS AND DIABETES IN RATS
The new drugs, derived from an herb that has been used medicinally since the Middle Ages, act on a specific opening, or ion channel, in the membranes of T cells. The study results appear Nov. 6-10 in the Early Online Edition of the Proceedings of the National Academy of Sciences.
In the process of developing the new drugs, the researchers confirmed that the ion channel targeted by the medications is responsible for a range of autoimmune diseases. The ion channel, known as Kv1.3, was first discovered in 1984 by a member of the research team, K. George Chandy of UC Irvine.
Heike Wulff, a UC Davis assistant professor of medical pharmacology and toxicology and co-author of the study, originally identified the molecules from the rue plant used to develop the drugs.
"Previously, the Kv1.3 channel was widely believed to be a good target for treating autoimmune diseases, but until now, scientists had not established that it is," said Wulff. "This study really confirms it."
The researchers also found that the Kv1.3 channel is involved not only in multiple sclerosis, but other autoimmune diseases, such as rheumatoid arthritis and Type 1 diabetes. In addition, the new medication tested by the researchers overcomes limitations and drawbacks of a previously developed drug aimed at ion channels involved in autoimmune diseases.
An ion is a charged atom, and an ion channel is an opening in the wall of a cell that connects the cell's interior to the environment surrounding it. As many as a million ions can pass through an ion channel in one second. Ion channels allow different ions to pass through. For example, an ion channel may allow potassium ions to pass through, but not sodium ions.
Wulff and her fellow researchers focused their attention on ion channels of in effector memory T cells, which belong to a group of white blood cells known as T lymphocytes. T cells have been implicated in autoimmune diseases, particularly multiple sclerosis. These cells invade the central nervous system and stimulate other cells to destroy the myelin sheath of neurons.
Potassium channels regulate the activation of T cells and, in previous research, Wulff had found that one of the 76 different potassium channels in humans is overly abundant in T cells that have gone awry. These cells attack the body's healthy tissues and cause several autoimmune diseases.
Earlier research by Wulff had identified a small molecule from the rue plant that blocked this potassium channel. However, the chemical had a low affinity for the potassium channel and caused unwanted side effects.
In the new study, Wulff and her colleagues developed new drugs from the rue plant, known as PAP-1, and from the venom of the Cuban sea anemone, known as SL5. They used the drugs to improve arthritis in rats and reduce the incidence of diabetes in rats prone to the disease. Repeated doses of the drugs produced no harmful side effects.
The new drugs are an improvement over the earlier drugs in another important way, Wulff said. The older drugs were not water-soluble and had other physical properties that made them impossible to give to animals. The new drugs, on the other hand, can be absorbed from the intestines and taken orally.
"The properties that allow these Kv1.3 blockers to be absorbed from the gut present tremendous opportunities for the development of an oral medication that people can take to treat arthritis, diabetes and other autoimmune diseases linked to the Kv1.3 channel," Wulff said.
Wulff and her fellow researchers are planning to further evaluate the toxicity of PAP-1 and SL5 and perform toxicity studies in animals, which are required by the Food and Drug Administration before a new drug may be tested in humans. In other studies, the researchers will test PAP-1 in animal models of organ transplant rejection and myasthenia gravis. In another study previously conducted by the researchers, they showed that PAP-1 has potential for use as a cream for psoriasis, another T-cell-mediated autoimmune disease.
"While it is always difficult to predict, if everything goes well, we might have an experimental medication ready for testing in humans in two-to-three years," Wulff said.
Other UC Davis members of the research team were Peter Havel, a research endocrinologist in the Department of Nutrition, and Stephen Griffey, director of the Comparative Pathology Laboratory in the School of Veterinary Medicine.