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Incurable Blood Cancer Treatment Could Be In Sight

One of the characteristics of Mantle Cell Lymphoma (MCL) is the aggressive over-production of a cell-proliferation protein due to an overactive gene. Now scientists at Tel Aviv University in Israel, in collaboration with industry, have developed a new class of drugs based on RNA interference that can repair or destroy the faulty proteins, bringing closer the day when this incurable blood cancer can be treated.

Scientists already know that a key feature of MCL, an incurable B cell non-Hodgkin's lymphoma with a mean survival span of 5 to 7 years, is an over-expression in CCND1, the proto-oncogene that encodes for the protein Cyclin D1 (cycD1). The protein controls the production of B Lymphocytes, cells responsible for generating antibodies.

The over-expression leads to a 3,000 to 5,000-fold increase in cell-proliferation, explains Dan Peer, a professor in Tel Aviv University's Department of Cell Research and Immunology, in a press statement issued on Tuesday.

Various attempts have already been made to knock out the gene as a way to stop the over-proliferation, but they failed. This has led to the belief that Cyclin D1 would not be an effective target for therapies.

But Peer and colleagues decided to try a slightly different approach, instead of knocking out the gene, why not try to influence protein production by interfering with gene expression? RNA Interference Approach RNA interference (RNAi) is a natural process in living cells that modifies gene expression. So, for example, if a gene is coding for a protein that may be harmful in some way, RNAi provides a means to modify it.

Using RNAi, Peer and his team found a way to reprogram cells to act normally, and to trigger cell death in faulty proteins.

The new class of RNAi drugs they developed kills off the mutated protein and stops the over-proliferation of cells. They write about their method, which they proved in lab experiments with human cells, in the online open access journal PLoS ONE.

The university researchers turned to two world-expert US companies in RNA to help them: Alnylam Pharmaceuticals in Cambridge, Massachusetts and Integrated DNA Technologies in Iowa, both of which donated their time and resources to the project.

They worked in parallel and designed potent RNAi sequences that stopped the production of Cyclin D1.

In their method, the RNAi drugs target faulty Cyclin D1 within cancerous cells. The cells detect they are being targeted and prevented from multiplying, and trigger their own cell death or "apoptosis". "We Want to Cure this Disease" "Ultimately, we want to be able to cure this disease, and I think we are on the way," says Peer.

He also hopes the study will prompt scientists who had given up on trying to find ways to treat MCL via faults in this protein to try again.

The team is now looking for ways to breed mice with MCL so they can test the new drugs in animals. This is the normal course for testing a new therapy: lab tests in human cells and animal studies, before taking it to trial in humans.

Peer says this would be the first time that a test has used mice with MCL, which has been a drawback in previous studies.

Animal testing will allow his team to carry out a more careful and detailed study of the drugs before taking them to clinical trial. Nano-Submarines Another avenue the team is investigating is the use of nanotechnology, something Peer has done extensive work in. The idea is for nano-sized medical "submarines" to navigate to the source of the disease, then drop their drug payload inside the targeted cells or proteins.

Nano-submarines is just one example of how scientists are turning to various ways of using nano-technology in medicine.

Funds from the Lewis Trust and the Israeli Science Foundation helped pay for the study.

According to the Leukemia and Lymphoma Society, there are three thousand new cases of Mantle Cell Lymphoma (MCL) in the US every year. The disease is devastating, and new therapies are sorely needed.

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