# DEFINING RISK FACTORS FOR NF1-OPTIC GLIOMA

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $348,844

## Abstract

Project Summary
As we enter into an era of personalized medicine, it becomes increasingly important to define the factors that
confer disease risk and outcome. Since these determinants cannot be easily controlled in human
epidemiological studies, genetically-engineered mouse (GEM) strains provide mechanistically-tractable
platforms to define the factors underlying disease heterogeneity and translate them to risk assessment tools
and treatments. Pediatric low-grade brain tumors (gliomas) represent one such challenging disease with
respect to predicting clinical progression, optimizing treatment, and improving neurologic outcome. In the most
common inherited cause for pediatric low-grade glioma, neurofibromatosis type 1 (NF1), 15-20% of children
develop optic pathway gliomas (OPGs), leading to visual decline in 30-60% of affected individuals. However, it
is not currently possible to predict which child with NF1 will develop an OPG or who will experience visual
decline or blindness from their tumor. Our ability to identify those children at greatest risk for OPG development
and vision loss would provide important clinically-meaningful prognostic information to guide clinical care for a
pre-verbal patient population in which accurate visual assessments can be challenging. Recent observations
suggest that the specific germline NF1 gene mutation may be one risk factor for OPG development, whereas
patient sex influences OPG-associated visual decline. In this regard, children with NF1-associated OPGs are
more likely to harbor specific types of germline NF1 gene mutations (5' end frameshift mutations). In addition,
we have recently shown that female children and mice with NF1 more frequently experience visual loss from
their OPGs. Based on these provocative findings, we hypothesize that the particular germline NF1 gene
mutation and gonadal sex hormones are independent risk factors for OPG development and progression,
respectively. In this proposal, we aim to critically determine how the specific NF1 gene mutation dictates OPG
formation and define the molecular basis for the observed sexually-dimorphic OPG-associated vision loss
using a novel series of Nf1 GEM strains and approaches. The resulting outcomes will be leveraged to
preclinically evaluate new approaches to identifying children with NF1 at risk for OPG development and vision
loss as well as potential alternative therapeutic approaches for attenuating or preventing NF1-OPG-related
visual decline.

## Key facts

- **NIH application ID:** 9987576
- **Project number:** 5R01CA214146-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** David H Gutmann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $348,844
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987576

## Citation

> US National Institutes of Health, RePORTER application 9987576, DEFINING RISK FACTORS FOR NF1-OPTIC GLIOMA (5R01CA214146-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9987576. Licensed CC0.

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