By Avigayil Kadesh
In autoimmune diseases such as Crohn’s, lupus and rheumatoid arthritis, the body’s immune system mistakenly attacks healthy tissue rather than invading germs. Researchers haven’t figured out how to reverse this haywire process. However, following years of hard work in the lab, it looks like an Israeli team has achieved a breakthrough.
Scientists from the Weizmann Institute
in Rehovot managed to “trick” the immune systems of mice into targeting an enzyme known as MMP-9. This enzyme is one of a family of proteins essential for processes including wound healing. But when it gets out of control, MMP-9 facilitates autoimmune disease as well as the spread of cancer.
As reported in an article in the December 23 issue of the journal Nature Medicine, Prof. Irit Sagi
and her research group spent years looking for ways to block MMP-9. They first tried making a synthetic drug molecule targeting MMPs in the same way that the body’s own MMP inhibitors, known as TIMPs, are designed to do. But the drug couldn’t mimic nature well enough, and also had extremely severe side effects.
Clearly, an alternative approach was called for. That became the years-long focus of Netta Sela-Passwell, a graduate student in Sagi’s lab. Her solution eventually took shape as a sort of vaccine to trick the immune system into creating natural antibodies against MMP-9. It works in the same way that a vaccine containing a dead virus induces the immune system to create antibodies ready to attack the live virus.
Outwitting the autoimmune process
Together with Prof. Abraham Shanzer of the Weizmann’s organic chemistry department, the researchers created an artificial version of the metal zinc-histidine complex at the heart of MMP-9.
They then injected these small, synthetic molecules into mice.
Blood tests done on the mice afterward showed the presence of antibodies the scientists dubbed “metallobodies,” which are similar to TIMPs in structure and function. In lab experiments, they saw that the metallobodies bound tightly to both the mouse and human versions of MMP-2 and MMP-9.
Illustration of the Weizmann “metallobody” at work.
Photo courtesy of the Weizmann Institute.
The next step was to induce an inflammatory condition that mimics Crohn's disease in mice, and watch how the metallobodies did their job. To the scientists’ great delight, the Crohn’s symptoms were successfully prevented.
“We are excited not only by the potential of this method to treat Crohn’s, but by the potential of using this approach to explore novel treatments for many other diseases,” said Sagi, who is president of the Israeli Biophysical Society.
Yeda Research and Development Company
, the technology transfer arm of the Weizmann Institute, has applied for a patent for the synthetic immunization molecules as well as the generated metallobodies.
Also participating in this research, supported by several charitable funds and donors, were Orly Dym, Haim Rozenberg, Raanan Margalit, Rina Arad-Yellin and Tsipi Shoham of the structural biology, immunology and biological regulation departments, Raghavendra Kikkeri of the organic chemistry department, Miriam Eisenstein of the chemical research support department, Ori Brenner of the veterinary resources department and Tamar Danon of the molecular cell biology department.