Research’s Next Top Model
Cincinnati Children’s scientists find the ideal model for neurofibromatosis
For researchers working to understand and develop treatments for complex genetic diseases, creating a mouse model that faithfully mimics the human disease is an elusive goal but one that is paramount to the success of their work. Some, like Cincinnati Children’s cancer biologist Nancy Ratner, PhD, see this goal become a reality.
For more than two decades, Nancy Ratner, PhD, has sought the perfect model to study neurofibromatosis.
Earlier this year, Dr. Ratner and her colleagues revealed that they have created an improved mouse model for the genetic condition neurofibromatosis type 1 (NF1). The model will both enhance scientific understanding of the disease and significantly accelerate the pace for developing therapies to treat it. The new model was unveiled in a multi-institutional study published in the February edition of the journal Cancer Cell.
Starting From Scratch
Neurofibromatosis type 1 (NF1) is an inherited disorder that causes tumors to grow mixed with nerves. The condition affects one of every 3,000 people worldwide, with nearly 90 percent of those affected developing the benign peripheral nerve tumors called neurofibromas.
For Dr. Ratner, creating such a neurofibroma model has been a driving force in her work since she decided to focus on neurofibromatosis more than two decades ago. There was little known about the disease at that time.
“I was invited to speak about my work on nerve axon-glial interactions in 1985 at the very first meeting ever on neurofibromatosis. It was a National Academy of Sciences meeting in New York,” Dr. Ratner says. “At that time, there was almost no research on neurofibromatosis and this meeting brought together some biologists studying things that were thought to be relevant with the few working on neurofibromatosis.”
Her training as a developmental biologist made Dr. Ratner curious about what might predispose a person to neurofibroma formation. “Right around that time, I was starting my own lab and I decided to focus on neurofibromatosis. Our work’s been devoted all these years to trying to study cells from neurofibromas and to make better and better models of neurofibromatosis.”
Many NF1 patients conduct normal lives with the disease, with the primary manifestation being numerous soft brown pigment spots on the skin, and small nerve tumors under the skin.
Other patients, however, develop learning disabilities, scoliosis, leukemias or benign brain tumors as children, and are at risk for cardiovascular problems and malignant tumors as adults. Other children develop large plexiform neurofibromas which are at risk for later malignancy.
Neurofibromas can sometimes be surgically removed, or can be targeted with chemotherapy or radiation in the rare event they become malignant. There is currently no treatment to prevent new neurofibromas from growing or stop growth of existing nerve tumors.
An Accurate Replica
Nor, until now, has there been a reliable model to study them. Investigators identified disease-causing mutations in the NF1 gene in 1990, but they have struggled to create a mouse model that accurately reproduces the human disease. “In the past, we had some culture models, but we really weren’t entirely sure how well they mimicked the human disease,” explains Dr. Ratner. “So we used them, but with some trepidation.”
Dr. Ratner and her team generated mice in which NF1 is turned off at a specific time, in a discrete cell type during development, creating a window between six and 10 months in which researchers can test potential therapies.
“Now we have something that really looks like a clear-cut mimic,” she says. “And, it provides a relatively rapid screening model. With the model, we can measure tumor growth and tumor shrinkage over the course of months.”
A Giant Step Forward
With this new model at their disposal, Dr. Ratner says, “the sky’s the limit on what we can test. The advantage of the new mice is that we can be more aggressive and see what’s really effective. So we can try all the things that are available already and then move on to new possibilities.”
To move the testing process forward, Cincinnati Children’s has recently become involved in a new pre-clinical consortium funded by the Children’s Tumor Foundation. The Foundation recently gave $5 million over three years to four groups, including Cincinnati Children’s. “They’ve given us money to use this new model to start testing specific drugs,” says Dr. Ratner. Timothy Cripe,MD, PhD, is the principal investigator for this work.
Dr. Ratner envisions a time when this new model will yield dramatic results.
“I think most people don’t think we’re going to find a magic bullet that’s going to shrink the tumor and make it be gone forever,” she says. “I am more optimistic because I think if you give treatment early enough, you could keep it exceedingly small or even prevent formation of the tumor.”
