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Inflammatory cells highly promising target in NF 1
Scientists at the Indiana University School of Medicine are closing in on potential treatments for neurofibromatosis, a
genetic disease that afflicts 100,000 Americans with nerve tissue tumors, some of which become cancerous.
Neurofibromatosis can leave its patients miserable and debilitated with chronic itching or pain from disfiguring tumors.
Infants affected by the disease face possible paralysis or damage to the brain and other organs.
The disease frustrates doctors because there's no effective treatment even though the responsible gene was identified more
than a decade ago. Currently little can be done to treat a disease that affects more people than cystic fibrosis, hereditary
muscular dystrophy, Huntington's disease and Tay Sachs combined.
Now, however, research by IU School of Medicine scientist D. Wade Clapp, M.D., and his colleagues David A. Ingram, Jr., M.D.
and Feng-Chun Yang, M.D., Ph.D., have identified a promising target to treat the symptoms of neurofibromatosis. They hope to
begin preliminary testing in humans by the end of this year, and are experimenting with potential drug compounds now.
Dr. Clapp, professor of pediatrics and of microbiology and immunology, said one target of their efforts will be mast cells,
which are immune system cells that are involved in asthma and allergic reactions. Mast cells play a role in neurofibromatosis
because they also are involved in blood vessel formation -- and tumors need blood vessels in order to grow.
"We are beginning to have a better understanding of cell to cell interactions that lead to the development of tumors and are
poised to answer some of the most perplexing questions that underlie neurofibromatosis," said Dr. Clapp.
"Our work may well be applicable to other types of tumors such as breast and ovarian cancers, because inflammatory cells play
an important role in tumor formation in these malignancies."
Neurofibromatosis results from mutations in a gene called NF 1. In humans, NF 1 mutations resulting in neurofibromatosis
occur in one in 4,000 births, equally affecting both sexes and all races and ethnicities. It is the most common neurological
disorder caused by a single gene. Some NF 1 mutations are inherited, but the NF1 gene is so large that many mutations occur
spontaneously rather than being passed from parent to child.
Everyone has two copies of the NF 1 gene, which produces a protein called neurofibromin that controls cell division. If both
NF 1 genes are defective, not enough neurofibromin is produced, cell division takes off and tumors develop.
"It's like an engine being driven at full speed," said Dr. Clapp.
To encourage development of the blood vessels they need, the tumors emit chemical signals that cause the mast cells to
congregate in tissues surrounding the tumors. The mast cells create chemicals called growth factors that enable the creation
of blood vessels.
The IU investigators now are identifying drugs that can disrupt the function of mast cells and their proteins in ways that
they believe will starve the tumors.
"It's much easier to develop targets against a non-malignant cell than it is the malignant cell itself," said Dr. Clapp.
That's because the biological activities of non-malignant cells are stable, while malignant cells are constantly changing due
to the genetic instability common to tumors.
By using drugs that target the mast cells' ability to promote blood vessel growth, Clapp and his colleagues hope to prevent
tumors from getting larger. Eventually, with continuing treatment, they hope the tumors will shrink or die from lack of blood
vessel support.
Neurofibromatosis gets its name from neurofibromas, the disfiguring and often painful tumors that grow along nerve coverings
and form on or under the skin. In most patients, the tumors begin to appear in adolescence or adulthood. A patient may
develop hundreds of neurofibromas over a lifetime.
Some NF 1 patients also develop numerous light brown (café-au-lait) spots on the skin, enlargement and deformation of bones
and curvature of the spine (scoliosis), and in many instances, learning disorders. Occasionally, tumors may develop in the
brain, on cranial nerves, or on the spinal cord.
However, a rare form of the disease occurs in infants and young children, with tumors growing on major nerves, such as the
sciatic nerve that connects the spinal cord with the leg and foot muscles. The tumors can interfere with the function of the
brain and other organs, or prevent patients from walking.
"Those are particularly tough problems. They're very challenging to treat surgically, and radiation and chemotherapy don't
help," said Dr. Clapp.
Eric Schoch or Cindy Fox Aisen - caisen@iupui.edu
Indiana University
Celule inflamatorii foarte promiþãtoare þintã în NF 1 - Inflammatory cells highly promising target in NF 1 - articole medicale engleza - startsanatate