The proposed studies will establish a treatment strategy for learning disabilities associated with neurofibromatosis. It is well known that people with neurofibromatosis suffer from a variety of learning problems. The biologic basis for these disabilities is difficult to study in humans. Animal models have therefore been employed to conduct this research. Both mice and fruit flies with mutations in a neurofibromatosis gene have memory and learning problems that can be studied. In mice, the research has suggested that the Neurofibromin protein is required in a specific brain structure called the hippocampus that is important for learning and memory, including spatial learning and memory. Learning and memory functions in fruit flies are also impaired by mutations in the same neurofibromatosis gene. In fruit flies it has been possible to show that a drug developed to treat cancer can effectively treat the learning and memory problems associated with neurofibromatosis. This drug inhibits a molecule that can cause cancer when it is unregulated. It also inhibits the normal molecule. We have studied the function of the normal molecule in learning and memory in mice. Similar to fruit flies, we have found that inhibition of this molecule can enhance retention of spatial memory in mice. We therefore propose to test the applicability of this strategy to treat mice engineered to have neurofibromatosis. We will test the ability of this drug to improve learning and memory in mice with mutations in the neurofibromatosis gene.

Ultimately, this research will lead to an effective treatment for the learning disabilities associated with neurofibromatosis. The drug that has been applied in fruit flies can be orally administered to mice. Either this drug or a similar one will improve or cure the learning disability found in a majority of neurofibromatosis patients. The patients who are likely to benefit are those with mutations in Nf1, 90% of neurofibromatosis patients, who suffer from learning disabilities. The benefits will be to enable them to learn and to function intellectually at higher levels. The time frame for achieving these patient-related outcomes could be very short. A similar drug has already been approved by the Food and Drug Administration (FDA) for treating cancer. We are not using this drug because it does not get into the brain. If the alternative drug we are testing works, it would need to obtain FDA approval. The issues of human tolerability and the process required for FDA approval would determine the time frame for achievement of a patient-related benefit.

The field of neurofibromatosis research will be greatly advanced by clarification of the mechanism underlying learning disabilities associated with Nf1 mutation. We have studied the molecule that is targeted by the drug. Its function is not well understood in the mammalian brain. The connection of this molecule to Neurofibromin will provide new insights into Neurofibromin function in learning and memory. It will also provide new therapeutic targets for treatment of neurofibromatosis.