# Inhibition of NF1 Protein Degradation as a Treatment for NF1 Haploinsufficiency

> **NIH NIH R43** · INFIXION BIOSCIENCE, INC. · 2022 · $143,781

## Abstract

PROJECT ABSTRACT. Haploinsufficiency plays a crucial role in Neurofibromatosis (NF1), an autosomal
dominant genetic disorder impacting over 120,000 Americans. Current therapeutic approaches target
downstream components of NF1 signaling, for example MEK inhibition in tumors, thus failing to address the
broad range of signaling and symptoms associated with NF1 mutations. Given that NF1 is characterized by
both autosomal dominance and haploinsufficiency (lack of normal protein), inhibiting NF1 protein degradation,
causing a net increase in NF1 protein, has the potential to alleviate a broad range of NF1 symptoms and halt
overall disease progression. Infixion proposes to identify and validate genes involved in NF1 protein
ubiquitination and degradation, and to build a protein-tagged reporter assay to screen the impact of known
drugs on NF1 protein levels, with a focus on modulators of NF1 protein degradation. By identifying candidate
drugs inhibiting NF1 ubiquitination, we target an increase in overall NF1 protein, and thus a normalizing of Ras
(and other) pathway signaling in individuals with NF1. We propose this as a novel path of NF1 drug discovery,
with potential impact on a broad range of NF1 patients and symptoms, in a preventative manner, and
applicable to the very wide spectrum of unique NF1 genetic mutations.
Research Background. Increasing NF1 expression via transfection reverses abnormal Ras activation
resulting from NF1 loss (Wallis, 2018; Mellert, 2018). Increased protein expression in other genetic conditions
such as Willams-Beuren Syndrome, and Supravalvular Aortic Stenosis compensates for haploinsufficiency
(Giordano, et al. 2012). Lastly, overcoming haploinsufficiency in other autosomal dominant conditions (Sim1;
Pax6 genes) have shown an ability in vivo to correct symptoms. (Matharu, et. al. 2019; Rabiee, et. al. 2020).
Specific Aims. 1) Identify regulators of NF1 protein stability using siRNA libraries as a genetic (knock-down)
screen in NF1-relevant cell types. Identifying regulators of NF1 ubiquitination and subsequent degradation will
allow for rational selection of additional libraries to screen for compounds to increase NF1 protein. 2) Construct
an assay, engineering the endogenous NF1 gene to tag the NF1 protein, in a well characterized, publicly
available (ATCC), immortalized NF1 +/- Schwann cell line. Validate assay using compounds already verified by
Infixion to increase NF1 protein levels. 3) Deploy NF1 protein stabilization assay to screen a 13,000+
compound repurposing library of known drugs available from Scripps Research Institute (known as ReFrame),
and other targeted libraries. The top hits from these screens will be evaluated utilizing immortalized Schwann,
primary fibroblast and iPSC derived NF1+/- cells, for the following: a) ability to induce NF1 protein expression
using Westerns/ELISA, b) impact on Ras signaling (pERK, ELK-1, AKT, etc.) utilizing a targeted quantitative
mass spec proteomics assay, c) impact on ...

## Key facts

- **NIH application ID:** 10490386
- **Project number:** 5R43NS124424-02
- **Recipient organization:** INFIXION BIOSCIENCE, INC.
- **Principal Investigator:** Michelle Mattson-Hoss
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $143,781
- **Award type:** 5
- **Project period:** 2021-09-20 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10490386

## Citation

> US National Institutes of Health, RePORTER application 10490386, Inhibition of NF1 Protein Degradation as a Treatment for NF1 Haploinsufficiency (5R43NS124424-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10490386. Licensed CC0.

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