# Gene Therapy for the Treatment of Neurofibromatosis Type I (NF1)

> **NIH NIH F99** · DUKE UNIVERSITY · 2022 · $34,748

## Abstract

PROJECT SUMMARY/ABSTRACT
Neurofibromatosis Type I (NF1) is a cancer predisposition syndrome caused by an autosomal dominant mutation
in the gene, NF1, that effects 1 in 2,500 people worldwide. NF1 encodes for neurofibromin, a GTPase-activating
protein that negatively regulates the Ras signaling pathway, such that loss of NF1 results in Ras hyperactivation
leading to uncontrolled cell growth and proliferation. While NF1 is characterized by a wide host of symptoms, the
most concerning are plexiform neurofibromas, which affects 30-50% of patients. Furthermore, 8-13% of patients
will also develop malignant peripheral nerve sheath tumors (MPNSTs), which is the main cause of morbidity in
NF1 patients, with only 20-50% of patients surviving 5 years post-diagnosis. While therapeutic strategies
targeting Ras signaling can provide some benefit for NF1 patients by shrinking plexiform neurofibromas, gene
editing is the only strategy that can address the root cause of NF1 by correcting mutations in NF1. However,
many of the existing gene editing and gene therapy strategies cannot be adapted to the treatment of NF1.
Additionally, the amount of neurofibromin restoration required to achieve clinical improvement is unknown; a gap
in knowledge that hinders the development of optimal therapeutic strategies for NF1. The aim of the F99 phase
of this fellowship is to develop a CRISPR-based system to correct pathogenic mutations in ~90% of the NF1
patient population by inserting a 4.5 kb superexon sequence into the mutated NF1 gene to restore the correct
NF1 sequence. Experiments in HEK293T cells have shown successful integration and transcription of the
superexon as well as correct splicing to the endogenous exon. This is predicted to create functional
neurofibromin, reduce Ras signaling to basal levels, and reduce the size of plexiform neurofibromas in a mouse
model of NF1. The aim of the K00 phase of this fellowship is to interrogate the amount of neurofibromin required
to restore function in two different biological contexts: plexiform neurofibromas and MPNSTs. Novel doxycycline-
inducible cell and mouse models will be generated to test the hypothesis that there is a threshold required to
restore tumor suppression, but that this amount will vary depending on the genetic and biological context of the
tumor. This work will directly address the need for novel therapeutics for plexiform neurofibromas (F99
phase) and will fill a critical knowledge gap by interrogating the amount of neurofibromin needed to
restore function in the context of plexiform neurofibromas and MPNSTs (K00 phase). Together, this
knowledge will not only provide a foundation for the development of novel therapeutics for NF1 and related
cancers, but also other cancer pre-disposition syndromes. The proposed training plan will also provide
exceptional training by leaders in the genetic engineering and cancer biology fields, positioning the
applicant to become a successful independent researcher at the ...

## Key facts

- **NIH application ID:** 10529664
- **Project number:** 1F99CA274707-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Madeleine Janette Sitton
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $34,748
- **Award type:** 1
- **Project period:** 2022-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10529664

## Citation

> US National Institutes of Health, RePORTER application 10529664, Gene Therapy for the Treatment of Neurofibromatosis Type I (NF1) (1F99CA274707-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10529664. Licensed CC0.

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