Abstract
Purpose :
Autosomal dominant neurofibromatosis type-1 is a genetic disorder caused by a mutation in the neurofibromin tumor suppressor gene that results in multiple benign optic gliomas in the visual pathway, leading to compressive optic neuropathy and vision loss. Current therapies for NF1 have poor outcomes; therefore, new treatments are needed. Over the past two decades, seminal studies in rodents from our and others’ labs have identified RGC replacement strategies such as stem or primary cell transplantation. However, most of this data was developed in acute trauma models of optic nerve crush, which may or may not translate to the axon damage and retinal and optic nerve environment in NF1 optic glioma, and it is unclear if the cell transplantation itself could harm the remaining endogenous host cells in the retina.
Methods :
Using a mouse model of NF1, we examined the effect of cell transplantation on both control wild-type and NF1 hemizygous mice with optic pathway gliomas. Primary RGCs taken from universal GFP mice were mixed with the red calcium indicator jRGECO1a and injected into the vitreous. We then performed ex vivo two-photon recordings in response to whole field light flashes of a dim green and bright UV light to drive the scotopic and photopic pathways.
Results :
With this method, we could observe ON, OFF, and ON-OFF light responses to a 1-second light flash. We found little difference in host RGC response measures between wild-type and NF1 glioma mice without cell transplantation. However, donor cell transplantation increased the proportion of non-responsive RGCs and decreased the fraction of ON-OFF RGCs in wild-type mice. In contrast, there was little effect on host RGC response characteristics in NF1 glioma mice other than a shift from rod-responsive to cone-responsive ON RGC population. We also found that host RGCs in NF1 heterozygous mice without tumors respond more similarly to the wild-type control mice than to the NF1 glioma mice.
Conclusions :
Thus, an RGC transplant may have a detrimental effect on the intact retinal circuitry of endogenous RGCs. We hypothesize that the transplantation of donor RGCs into the NF1 glioma mouse has little impact on host RGCs due to space created by RGC loss caused by the glioma. These results provide essential directions for ongoing study and promising opportunities for cell transplantation as a treatment option in NF1.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.