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Drug trials on mice are ‘almost human’ thanks to new Israeli technique

Posted By Leora Eren Frucht On April 30, 2006 @ 2:13 pm In | No Comments

Professor Karl Skorecki, director of the Technion’s Rappaport Research Institute, devised the novel experimental model, involving mice with human tissue. Six healthy young men volunteered to participate in a clinical trial of a new drug in Great Britain last month. Minutes after being administered a minute dose of the drug, all six volunteers were in excruciating pain, their necks severely bloated, and their vital systems failing. Rushed to intensive care, they were ultimately saved, but not before a close brush with death.

It was a particularly bad case of a Phase 1 clinical trial – aimed at proving safety and efficacy in a new pharmaceutical – gone wrong.

Now, a new Israeli method of testing experimental drugs could make such dangerous episodes a thing of the past, by providing a safer and more accurate method of gauging human responses to drugs – without risking human lives.

The new model, developed by researchers at Israel’s Technion Institute of Technology, and featured in the medical journal Cancer Research, constitutes an intermediary phase in drug-testing, that could be used after ordinary trials in mice, but prior to the costly and risky first clinical trials in humans.

The patented method involves injecting laboratory mice with human embryonic stem cells that subsequently develop into various human tissues. Scientists can gauge more accurately how people will respond to a new drug by monitoring its effect on actual human tissue – blood vessels, cartilage, fat tissue or connective tissue – all present in these mice.

Standard protocol enables a drug to enter Phase 1 clinical trials after the medication has proven to be safe and effective on ordinary laboratory mice. But frequently humans react very differently than mice, as in the particularly disastrous trial in the UK last month. In less dramatic trials, the drugs often prove to be safe, but simply ineffective on humans, compelling disappointed drug developers to go back to the drawing board.

It was this gap between mice and men that led Technion Professor Karl Skorecki, director of the Technion’s Rappaport Research Institute, to come up with the idea of the novel experimental model, involving mice with human tissue.

“It could ultimately lead to a new stage between animal and clinical trials,” said Dr. Maty Tzukerman, who carried out the project in the Technion’s Laboratory for Molecular Medicine.

In the Technion study, the mice were injected with undifferentiated human embryonic stem cells (from existing lines) to create a teratoma – a growth made up of a mixture of human tissue. These teratomas provided scientists with living human tissue wherein human cancer cells could grow.

These mice were then administered a drug that had proven effective in treating cancer in ordinary laboratory mice.

“In ordinary mice, the drug caused the complete disappearance of tumors. But in the mice with human tissue, we saw cells that were resistant to the drug,” says Technion Prof. Yoram Reiter, co-developer of the antibody-based drug used in the experiment. “Now we can try to study the cells that don’t respond and use this system to fine-tune the drug.”

Reiter called it “a novel and exciting development” that may help shed light on why, over the years, “scientists have managed to cure cancer in millions of mice, but not people.”

“We know that humans and mice don’t respond the same way,” he told ISRAEL21c. “But you want to know about the differences before you begin human trials. Now you can receive this information at a much earlier stage in drug development and improve the design of the drug, without resorting to trial and error on humans. You can see things you didn’t see before in existing models.”

The Technion study was featured in the “breaking news” section of Cancer Research, the journal of American Association of Cancer Research, which, in the same issue, ran an editorial questioning the existing protocol for clinical trials.

Tzukerman says the model could be used to test the effectiveness and side effects of any drugs slated for human use. She believes that it could have alerted researchers to the problems that arose in last month’s disastrous clinical trial in London. “I think with our system, we would have seen hints of the problems because of the diversity of human tissues in our model.”

The system could be especially useful for testing new cancer drugs. “Sometimes these are so dangerous that they will kill the patient before they harm the tumor,” notes Tzukerman.

In addition to screening drugs, the new system could also lead to the development of more effective cancer treatments. Human tissue provides a more conducive environment for the growth of tumors than does mouse tissue, explains Tzukerman. This often leads to overly-optimistic expectations of cancer drugs successfully tested on mice. “Our model could be used to explore what it is about human tissue that makes it so conducive to tumor growth. Those findings could then become the basis for developing new cancer drugs that will work effectively – specifically on human tissue.”

With the method showing such promise, Tzukerman hopes that a major pharmaceutical drug company will come on board and invest in developing the model for use in drug screening and improving medical treatment.

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