# Targeting the Notch3 Mutation to Cure Lehman Syndrome

> **NIH NIH R61** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $396,413

## Abstract

PROJECT SUMMARY/ABSTRACT
 Notch receptors play a critical role in cell fate decisions and in the regulation of osteoblast and osteoclast
differentiation and function. As a consequence, Notch plays an important role in bone remodeling. Lehman
Syndrome or Lateral Meningocele Syndrome is a devastating disease characterized by craniofacial
developmental abnormalities, bone loss and meningoceles. The syndrome is associated with mutations in
exon 33 of NOTCH3 upstream of the PEST domain leading to NOTCH3 stabilization and presumably gain-of-
function. We created a mouse model of Lehman Syndrome (Notch3tm1.1Ecan) that presents with osteopenia due
to enhanced osteoclastogenesis secondary to an increase in receptor activator of nuclear factor Kappa B
ligand (RANKL) expression by cells of the osteoblast lineage. The aim of the proposed research is to develop
ways to correct the skeletal manifestations of the disease by targeting the mutation with Notch3 antisense
oligonucleotides (ASO), a strategy that would be applicable to other genetic disorders of the skeleton. Our
specific aims are: Phase R61 Aim 1) To establish the efficacy of Notch ASOs in vitro and in vivo. In this initial
aim, we will test whether Notch3 can be downregulated in the skeleton and reverse the skeletal phenotype of
Notch3tm1.1Ecan mice; Aim 2) To establish that the Notch3tm1.1Ecan mutation can be targeted. We will determine
whether the Notch3tm1.1Ecan mutation can be downregulated specifically and the Notch3tm1.1Ecan skeletal
phenotype reversed by the administration of Notch36691-TAATGA antisense oligonucleotides; and Phase R33 Aim
3) To validate the ASO approach in NOTCH3 mutant-induced pluripotent (iPS) cells. In the R33 phase, we
intend to prove the utility of Notch3 ASOs in human cells by creating mutant iPS cell lines to study the efficacy
of Notch3 ASOs in downregulating NOTCH3 mutant alleles. The goals of the proposed work are to develop
specific antisense technology to treat skeletal manifestations of a devastating NOTCH3-associated disease, as
an initial step in the treatment of genetic disorders of the skeleton.

## Key facts

- **NIH application ID:** 10017652
- **Project number:** 5R61AR076747-02
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Ernesto Canalis
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,413
- **Award type:** 5
- **Project period:** 2019-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017652

## Citation

> US National Institutes of Health, RePORTER application 10017652, Targeting the Notch3 Mutation to Cure Lehman Syndrome (5R61AR076747-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10017652. Licensed CC0.

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