A new mouse study shows that a drug originally developed to stop cancerous tumors may hold the potential to prevent abnormal brain cell growth and learning disabilities in some children — if they can be diagnosed early enough.
According to researchers at the University of Michigan, the study sets the stage for more research on how the anti-tumor medication could be used to protect the brains of young children with the genetic disease neurofibromatosis 1, as well as other diseases that affect the same cellular signaling pathway.
Neurofibromatosis 1, or NF1, affects one in every 3,000 children, causing benign tumors to grow throughout the body, large head size, and other issues. Many children with NF1 also struggle with learning to read, write, do math, and behave well, according to researchers.
The impact on brain function is considered the most common — and most serious — issue caused by NF1, and often appears before other symptoms, except for brown patches on the skin that are often mistaken for birthmarks.
But while the tumors that erupt mostly later in life have been well-studied, NF1’s effect on brain function isn’t understood, the researchers note.
In the new study, the team studied neural stem cells — a kind of master cell that can become any type of neural tissue. In newborn mice with two copies of the genetic mutation that causes NF1, neural stem cells in a key area of the brain were far more likely to produce a kind of “helper” nerve cell called glia. They produced far fewer neurons, which send and receive crucial signals in the brain and body.
The scientists then took aim at the abnormal cell growth by giving the mice an experimental drug that has already been used in clinical trials for advanced cancer. Called PD0325901, the drug, known as a MEK inhibitor, blocks a specific action within cells called the MEK/ERK pathway.
Mice with the NF1 mutation that got the drug from birth developed normally, in contrast to mice with the same genetic mutations that didn’t receive the drug. The untreated mice appeared normal at birth, but within a few days had become hunched and scruffy, with abnormal growth of their bodies and brain cells.
The new paper’s senior author, Yuan Zhu, Ph.D., cautioned that the drug used in the study may not be appropriate to give to children who have been diagnosed with NF1. But other MEK inhibitors are being developed against cancer.
“The important thing is that we have shown that by treating during this brief window of time early in life, when neural stem cells in a developing brain still have time to ‘decide’ what kind of cell to become, we can cause a lasting effect on neural development,” said Zhu, an associate professor of internal medicine at the University of Michigan’s Medical School.
For a drug-based intervention to work, it would have to be given soon after developmental delays or benign tumors are noted in an infant or toddler, and after a NF1 diagnosis is made, Zhu noted.
About half of all people with NF1 inherited the mutated gene from a parent, while the other half develop it spontaneously in the womb. The disease affects individual patients very differently, he said, noting that one child born to a parent with mild NF1 can have a severe form of the disease, while their siblings can have mild or moderate symptoms.
Some people with NF1 have a “double hit” form of the disease, where both copies of the gene are mutated in certain body cells. The second mutation, according to the scientists, likely occurs in a neural stem cell that goes on to produce unusual neural cells. These patients often have severe learning disabilities, and an enlarged corpus callosum — a structure that connects the two halves of the brain and contains a large concentration of glia, the same cells that the mice in the new study had larger numbers of.
In addition to NF1, the researchers predict that their findings may have importance for patients with other genetic conditions that affect the same cell-signaling pathway called RAS. Collectively called neuro-cardio-facial-cutaneous (NCFC) syndromes or ”RASopathies,” they include Leopard syndrome, Noonan syndrome, Costello syndrome and Leguis syndrome. Like NFI, all these conditions affect the brains, circulation system and the face or head.
The study’s findings were reported in the journal Cell.
Source: University of Michigan