Posted January 17, 2023

Dr. Yuan Zhu, Children’s Research Institute
Dr. Wei Li, National Eye Institute
Dr. Han-Yu Shih, National Eye Institute

In fiscal year 2020 (FY20), the Neurofibromatosis Research Program (NFRP) began offering the Synergistic Idea Award (SIA) mechanism to support new ideas that represent synergistic approaches to Neurofibromatosis (NF) research involving multiple independent investigators. The overall goal of the SIA mechanism is for investigators to utilize their complementary and synergistic perspectives to address a central problem or question in the NF community.

For FY21, the NFRP funded one SIA to three independent investigators: Dr. Yuan Zhu of the Children’s Research Institute, and Drs. Wei Li and Han-Yu Shih of the National Eye Institute. Each investigator brings their own expertise and approach, including glioma, retinal biology and immunotherapy, to the project of studying optic tumor formation and inflammation in the NF population.

Nearly 20% of individuals with neurofibromatosis type 1 (NF1) develop tumors along the anterior visual pathway, involving optic nerves, optic chiasm, and/or optic tracts. These are referred to as NF1-associated optic pathway gliomas (NF1-OPGs), and one-third of NF1-OPG patients will develop progressive diseases, exhibiting vision loss, often to the point of legal blindness. Most NF1-OPGs are diagnosed in children younger than 7 years of age, with a peak incidence between ages 4-5, leading to a lifelong disability in nearly 7% of children with NF1. Unfortunately, surgery for NFI-OPGs is a high-risk treatment option and, consequently, human tumor tissues are rarely available for research. Radiation therapy is not always a viable option, either given potential to induce secondary malignant tumors. Although chemotherapy has tumor inhibitory effects, a mismatch between tumor shrinkage and the patient’s vision improvement after treatment highlights an urgent need to develop novel therapies for NF1-OPG. Recent studies suggest that loss of retinal ganglion cells (RGCs), the only nerve cells that connect the eye to the brain, is at least one of the mechanisms causing NF1-OPG-associated vision loss. The main objective of this proposal is to investigate the mechanism by which NF1-OPG causes death of RGCs and vision loss, as well as to develop novel therapeutic strategies that can preserve and/or restore vision.

In preliminary studies, the research team developed a series of genetically engineered mouse (GEM) models of NF1-OPG which established the first NF1-OPG model arising from the developing optic nerve and thus mimicking the pediatric nature of the disease. The current study will assess how the infiltration of microglia induced by Nf1-/- OPG cells induce OPG-associated axonal/myelin degeneration and RGC death during neonatal development. This study will use a green fluorescent reporter to isolate and characterize the abnormally infiltrating inflammatory cells and perform multi-omics experiments, including sophisticated genomic, epigenomic, and transcriptomic assays, to study them during OPG initiation and progression. The research team will attempt to eliminate or metabolically modulate the inflammatory cell population(s) as a means to prevent or alleviate OPG-associated nerve damage, RGC death, and vision loss. Finally, they will develop a novel model using the newly established genetic system called Mosaic Analysis with Double Markers (MADM) model, which tags sibling cells with or without Nf1 by green and red fluorescent protein, respectively. Isolation and genomic characterization of sibling Nf1-mutant and Nf1-wild-type cells will allow them to identify signals that induce inflammatory responses by mutant cells.

The development of the new series of NF1-OPG GEM models, including the MADM-NF1 model, will provide important research tools to investigate disease mechanisms and perform preclinical testing to develop novel therapies. This study, if successful, will provide a strategy to treat patients with NF1-OPGs before visual impairment becomes irreversible, which will significantly enhance the quality of life for the children afflicted with NF1-OPG, as well as many blinding diseases caused by the degeneration of RGCs.

Link:
Public and Technical Abstracts: Investigate and Target an Inflammatory Response During NF1-OPG Formation

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