Individuals with neurofibromatosis type 1 (NF-1) have a high risk of neurologic disabilities, including development of tumors in the nervous system, impaired mental and motor function, and difficulties with social interaction. One notable aspect of many of these neurodevelopmental deficits is their high prevalence and onset during childhood, suggesting that one or more developmental defects underlie the disease pathogenesis. For example, the most significant cause of lifetime morbidity associated with NF-1 patients is learning disabilities, which are found in 30% to 70% of patients during preschool years (2-6 years). Plexiform neurofibromas, the only benign peripheral nerve sheath tumors with a high risk of becoming malignant, are often identified during early childhood and thus have been proposed to be congenital. Optic pathway gliomas (OPGs), which are low-grade tumors arising within the visual system, are identified in 15% to 20% of NF-1 patients. Importantly, almost all NF-1-OPGs are identified in children younger than 7 years old, with a peak incidence between ages 4 to 5. These clinical observations suggest that early childhood is a time of high risk for many children with NF-1 who will develop tumors (e.g., plexiform neurofibroma and OPGs), as well as non-tumor-related problems such as learning disabilities.

Over the past 10 years, we have been using genetically engineered mouse (GEM) models to investigate the mechanisms causing developmental defects in NF-1 and develop a preventive treatment strategy to treat NF-1-associated disorders during a critical window of nervous system development. This proposal focuses on NF-1-associated OPGs (NF-1-OPGs). The major morbidity associated with NF-1-OPGs is vision loss, often to the point of legal blindness. However, the mechanisms underlying NF-1-OPG-related visual loss are not fully understood.

Since NF-1-OPGs often grow extensively along the optic pathway, surgery is not a good treatment option; consequently, human tumor tissues are rarely available for research. Radiation therapy is avoided when possible due to its potential to induce secondary malignant tumors and vascular abnormalities. Although chemotherapy can be effective in shrinking these tumors, there is frequently a mismatch between the amount of tumor shrinkage and patients’ vision after treatment. Recent studies suggest that loss of retinal ganglion cells (RGCs), the only nerve cells that connect the eye to the brain, is at least one of the mechanisms underlying NF-1-OPG-associated vision loss. Because chemotherapeutic agents are not expected to regenerate RGCs or re-establish neuronal circuits, the most effective therapy will be prevention or early intervention, i.e., delivering treatment before irreversible neurological deficits such as death of nerve cells occur.

We have developed GEM models for NF-1-OPGs that exhibit a two-step process of tumor development. Step one is a developmental defect during which a complete loss of NF-1 induces increased numbers of glial cells to grow in developing optic nerves and form OPGs. After OPG formation, step two involves OPG progression, during which a complex interaction between NF-1-deficient tumor cells and surrounding cells in the optic nerve causes inflammatory cell infiltration, axonal degeneration, loss of RGCs, and ultimately vision loss. This proposal will test the hypothesis that the developmental defects caused by NF-1 loss play a major role in the formation of progressive OPGs and represent a critical target for designing preventive and early interventional therapies. We propose two Specific Aims. In Aim 1, we will develop a series of novel GEM models of NF-1-OPGs to investigate the cellular targets and molecular mechanisms underlying abnormal glial cell proliferation induced by NF-1 loss during a critical window of optic nerve development. In Aim 2, we will develop preventive and early interventional therapies for improving visual impairment in a preclinical NF-1-OPG model. We will employ a series of anatomical, electrophysiologic, and behavioral assays to determine the time course of functional and behavioral deficits and correlate them to structural changes during OPG progression. We will then treat the NF-1-OPG model with an MEK inhibitor at different disease stages and determine optimal time windows for preventing and lessening visual impairment.

In summary, the proposed research will provide important insights into the role of NF-1 in two glial cell lineages during the development of optic nerves, as well as how its loss induces tumors in the developing optic nerves of young children. Importantly, this work will advance our ability to develop preventive and early interventional therapies for NF-1-OPGs, as well as potentially for other NF-1-associated complications. This novel therapeutic strategy is particularly relevant now, as clinical trials using MEK inhibitors are actively recruiting and treating patients with NF-1 who develop progressive OPGs as young as 1 year of life.