The Gilbert Family Foundation’s ( strives to support the 20% of neurofibromatosis type 1 (NF1) patients who develop optic pathway gliomas (OPGs). OPGs are slow-growing brain tumors that arise in or around the optic nerve and can cause the degeneration of the optic nerve and retinal ganglion cells (RGCs) leading to vision loss. VRI aims to develop new therapies to protect and restore vision for these patients.
: neuroprotection/neuroenhancement therapies (see GFF’s Vision Restoration Initiative: Exploring Neuroprotective/Neuroenhancement Therapies), exogenous RGC replacement therapy and endogenous RGC replacement therapy.
The latter two are both forms of regenerative therapies that aim to improve vision by regenerating RGCs and the optic nerve, which in turn could support recovery of function. Within VRI, exogenous RGC replacement occurs when new, wild-type RGCs are generated from human stem cells outside of the body and transplanted into the NF1-OPG patients, while endogenous RGC replacement will use small molecules, biologics, or gene therapies to stimulate a patient’s retinal stem cells to transform into new RGCs. They both are promising methods to provide vision restoration to NF1-OPG patients with extreme vision loss from severe optic nerve and RGC degeneration, in contrast to the neuroprotective/neuroenhancement therapies designed to support earlier and milder cases.
VRI has five projects focused on regenerative therapies: three for exogenous and two for endogenous RGC replacement therapies. The exogenous RGC replacement therapy projects aim to develop an RGC transplantation product that can integrate into patients’ retinal circuits. These three projects are led by Dr. Jeffrey Goldberg, Professor and Chair of Ophthalmology at Stanford University School of Medicine; Dr. Michael Young, Associate Professor of Ophthalmology at the Schepens Eye Research Institute, Inc.; and Dr. Donald Zack, Professor of Ophthalmology at Johns Hopkins University.
Each Dream Team member is addressing different but related challenges around differentiation and transplantation of RGCs. One aim in Goldberg’s lab towards developing a RGC differentiation protocol is focused on identifying relevant pathways to promote RGC specification to ensure that the RGC subtype generated is optimal for regrowth and integration as well as exploring methods to improve the efficiency of derivation. Similarly, Young’s lab evaluates different differentiation stages and RGC types to determine the ideal for transplantation and identifies variables in derived RGCs in mice, pigs, and non-human primates to support translation of the differentiation protocol to larger mammals. Zack’s lab aims to build upon their previous methodology to differentiate RGCs through extensive characterization of human stem cell-derived RGCs at the single cell level.
Furthermore, to ensure successful transplantation, Goldberg plans to use anatomic and functional assays to evaluate efficacy of RGC integration in vivo. Young’s lab is developing polymer composite grafts to be transplanted with the RGCs to improve their survival, engraftment, and differentiation, both for mouse and pig allografts. Lastly, Zack’s lab will screen to identify molecules and genes to support RGC axon growth to the brain, which is critical to restoring function further in the timeline. In summary, Goldberg, Young, and Zack have designed a collaborative set of experiments that explore or define a variety of critical mechanisms that will make exogenous RGC replacement possible.
On the other hand, the endogenous RGC replacement therapy projects seek to identify factors to enable human Muller glia, a retinal stem cell, to regenerate RGCs. These two projects are led by Dr. Dan Goldman, Professor of Molecular & Behavioral Neuroscience at the Regents of the University of Michigan; and Dr. Thomas Reh, Professor of Biological Structure at the University of Washington School of Medicine.
Zebrafish can generate new RGCs and recover vision after injury, and the Goldman lab has identified Muller glia as the retinal stem cell responsible. His project focuses on identifying gene expression changes and small molecules that are sufficient to drive retina regeneration in zebrafish in order to test and translate their effect on retina regeneration in mice. Reh’s lab will build off of these findings by using screens to find new pathways to stimulate RGC development in adult mice at a usable concentration. Together, Goldman and Reh will explore similarities and differences in regulatory factors between zebrafish and mice and identify key factors that can be used to promote RGC regeneration using endogenous Muller glia.
Through these collaborative projects for regenerative and neuroprotection/neuroenhancement therapies, VRI aims to address a significant gap in options for NF1-OPG patients with chronic vision loss. By taking a risk and investing in these innovative therapies of biological vision restoration, GFF aims to help discover and develop life changing treatments for a devastating manifestation of NF1.
 Fried, I., Tabori, U., Tihan, T., Reginald, A., & Bouffet, E. (2013). Optic pathway gliomas: a review. CNS oncology, 2(2), 143–159. doi:10.2217/cns.12.47