Approximately 1 in 5 patients with neurofibromatosis type 1 (NF1) develop optic pathway gliomas (OPGs).  These tumors develop along the visual pathway, often aggressively, and can cause degeneration of the optic nerve and retinal ganglion cells (RGCs), ultimately leading to vision loss.[1] While treatments exist aimed at reducing the size and growth of the OPG in hopes of minimizing potential vision loss, there are currently no disease modifying therapies that slow down the neurodegeneration and/or restore vision. The Gilbert Family Foundation (GFF) aims to address this gap in therapies that restore vision for patients with NF1-derived OPGs.

GFF’s Vision Restoration Initiative (VRI) is comprised of a consortium of experts in NF1, ophthalmology, and neuroscience. Nicknamed the ‘Dream Team’, this group is collaborating to develop three different types of products: neuroprotection/neuroenhancement therapy, exogenous RGC replacement therapy, and endogenous RGC replacement therapy.

Neuroprotection/neuroenhancement therapies are intended to protect and increase performance of injured RGCs and the optic nerve to improve visual function. These therapies target NF1-OPG patients with less severe tumors, or those who are in earlier stages of the disease and have experienced less optic nerve and RGC degeneration.  Six of the 12 Dream Team researchers focus on the development of these therapies, known as the ‘neuroprotection/neuroenhancement subgroup’ of VRI.  Research foci include identifying the cell intrinsic and extrinsic mechanisms of RGC loss, screening for new RGC survival promoting molecules, evaluating promising therapies to preserve injured RGCs and/or enable RGCs to regenerate damaged nerve fibers, and analyzing and validating preclinical models.

Two separate projects led by Dr. Andrew Huberman, Associate Professor of Neurobiology at Stanford University School of Medicine and Dr. Don Zack, Professor of Ophthalmology at Johns Hopkins University, investigate mechanisms of RGC loss that could help inform new therapeutic strategies.  The first focuses on the defining the retinofugal (eye to brain) pathway in NF1 mutant mice, particularly structural and molecular barriers that could hinder RGC axon regeneration at different stages of the disease.  Huberman also plans to test efficacy of enhancing retinal neural activity on regeneration of RGCs in NF1-OPG mouse models.  The Zack lab uses RGCs derived from human stem cells to better understand how NF1 mutations lead to RGC damage and cell loss.  This additional morphological and functional understanding of RGCs with NF1 mutations will be applied to develop a phenotypic profile to screen for new RGC survival promoter molecules to reverse disease-related defects.  These projects could inform understanding of visual defects in NF1-OPG patients to better define methods to reverse and overcome them, as well as provide a new, validated preclinical model in the iPSC-derived RGCs.

In addition, projects led by Dr. Larry Benowitz, Director of Labs for Neuroscience Research in Neurosurgery at Boston Children’s Hospital and Professor of Neuroscience/Neurosurgery/Ophthalmology at Harvard Medical School, Dr. Zhigang He, Research Associated at Boston Children’s Hospital and Professor of Neurology and Ophthalmology at Harvard Medical School, and Dr. Jeffrey Goldberg, Professor and Chair of Ophthalmology at Stanford University School of Medicine, aim to evaluate existing and novel neuroprotective and restorative therapies for RGC survival and RGC axon regeneration in NF1-OPG mouse models. Beyond studying previously validated treatments, the Benowitz lab will identify intrinsic and extrinsic mechanisms for RGC survival by investigating newly discovered regulatory pathways and could support better treatment strategies. Similarly, He’s lab will assess novel protective interventions targeting vulnerability of RGCs in presence of NF1-OPG in NF1 mutant models, as well as engineer an optimal axon growth program to ensure that transplanted RGCs, particularly those in the other VRI product types, will extend to reach targets for vision restoration.  Goldberg will translate of strategies for RGC survival and axon regeneration previously defined by optic nerve crush models to OPG injury and NF1-OPG models.  If effective, these therapies could be translated into a proof-of-concept study in a larger animal, used in combination with technologies developed by the other VRI subgroups to aid in axon extension, or even move directly to clinical studies.

Lastly, Dr. David Gutmann’s project, Director of NF Center and Donald O. Schnuck Family Professor Neurology at Washington University in St. Louis, aims to evaluate and test the NF1-OPG mouse model used by most of the projects described above to identify biomarkers of visual recovery.  This project aims to accomplish this by identifying a critical therapeutic window for lasting visual recovery and discovering a common RGC recovery pathway.  These findings will be validated by the other investigators using the models, and once confirmed, will be used to confirm efficacy of promising candidates in preclinical studies.  Taken along with the rest of the subgroup, this project is crucial to identify new treatments that could prevent or restore vision loss in NF1-OPG patients.

The neuroprotection/neuroenhancement subgroup meets regularly to discuss project statuses and challenges.  This not only supports principal investigators with direct collaborations in their projects, but also gives all the researchers the opportunity to revisit the primary goals of the subgroup and the initiative.

“It has been an honor to partner with the Gilbert Family Foundation and be a part of a team of talented group of collaborative researchers who have pooled their expertise and energies to develop strategies to improve vision in children with NF1 optic gliomas,” summarizes David Gutmann.  GFF can’t wait to see the results of these innovated studies and their potential to support NF1-OPG patients.

[1] 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