BIOL-05. SHORT TERM MEK-INHIBITOR TREATMENT IMPROVES OPTIC NERVE GLIA PATHOLOGY IN AN NF1-DEFICIENT MOUSE MODEL

摘要

BACKGROUND: Up to 20% of patients with Neurofibromatosis 1 (NF1) are diagnosed with optic pathway gliomas (OPGs) before 7 years of age, suggesting these tumors are formed during development. Yet, the early events that occur in the optic nerve (ON), resulting in OPG formation, have not been described. The aims of this project were to determine 1) how early, following loss of Nf1, glial abnormalities occur in the developing ON and 2) whether targeted treatment with a Mek-inhibitor during this timeframe can improve the abnormalities seen. METHOD: We used a well-established Nf1-deficient (Nf1-/-) conditional knockout mouse model that develops visible OPGs by postnatal day 60 (P60) to characterize the glial cell populations (Olig2+ oligodendrocytes and GFAP+ astrocytes) and proliferation rate (Ki67) in E17.5, P0.5, P2, and P5 nerves. We then treated mice from P0.5-P5 with PD0325901, using a Meki-in-milk protocol, and analyzed the nerves at P5 to look for response. RESULTS: Nf1-/- mice had an increase in both the Olig2+ and GFAP+ cell populations starting as early as P0.5. Consistent with a previously described migration pattern for oligodendrocytes, Olig2+ cells did not appear in the proximal nerve (near the retina) until between P2-P5. In contrast, Olig2+ cells in the mutant mice were present in the proximal nerve as early as P0.5, reaching their maximum number by P2 in this region. Interestingly, proliferation was only increased at P0.5, returning to control level at other time points. Following treatment with PD0325901, the mutant nerve glial phenotype was rescued to the control level at P5. CONCLUSION: These results provide support that the events preceding OPG formation begin early during ON development, and treatment with a Mek-inhibitor during this critical time window may prevent tumors from forming all together. Future studies will focus on whether this treatment strategy can prevent glial abnormalities long term.