ID #278 Glioma reduction is not required for visual improvement in a model of NF1 optic nerve glioma

Purpose

Neurofibromatosis type-1 (NF1) is a genetic disorder caused by mutations in the neurofibromin tumor suppressor gene. 15-20% of NF1 patients form optic pathway gliomas (OPGs)[1], which result in visual deficits due to damage to retinal ganglion cells (RGCs) whose axons travel through the optic nerve. Current treatments for vision loss in NF1 have poor outcomes; therefore, new therapies are needed. Here, we describe our efforts to treat vision loss in a mouse model of NF1.

Methods

We crossed two mouse lines, one that is hemizygous for NF1 (NF1KO/flx) with another that expresses the DNA-recombinase Cre in astrocyte precursor cells to remove the other NF1 allele. This double knockout of NF1 leads to glioma formation in the optic nerve (“NF1-OPG mice”). To evaluate vision, we used optomotor reflex to measure visual acuity, pupillary light reflex to evaluate light sensitivity, and looming object fear response to assess contrast detection. In a masked experiment, we injected a control virus (AAV2-mSncg-Luciferase) or one that expresses constitutively active calcium/calmodulin-dependent protein kinase II (AAV2-mSncg-CaMKiiα).

Results

NF1-OPG mice have severe visual defects in both looming and optomotor reflex responses; however, the pupillary light reflex is intact. Immunofluorescence labeling of RGCs showed 16% lower RGC density, with some regions having over a 50% loss in NF1-OPG mice. We found a significant defect in the optomotor reflex that improved with treatment. Despite this protection against functional vision loss, there was no increase in RGC density between control and CaMKiiα-treated NF1-OPG mice.

Conclusions

Visual deficits in NF1-OPG mice can be prevented by treatment with constitutively active CaMKii gene therapy, even without neuroprotection. This suggests that vision loss is due to additional disruptions in neural signaling or circuitry. Therefore, effective strategies for treating NF1 patients must consider the role that NF1 plays in neuronal signaling.

1. 1. Listernick, R., Charrow, J., Greenwald, M. & Esterly, N. Optic gliomas in children with neurofibromatosis type I. The Journal of Pediatrics 114, 5 (1989).