# Progeria and Vasculature: Investigating Genetic Effects and the Potential of Genome Editing for Treatment

> **NIH NIH F31** · DUKE UNIVERSITY · 2022 · $46,752

## Abstract

Project Summary
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, accelerated-aging disease that leads to death in
patients by their early teens. It is caused by a de novo point mutation in one allele of the LMNA gene. LMNA is
typically alternately spliced to produce Lamins A and C which are responsible for stable nuclear envelope
structure. The HGPS mutation results in a truncated, farnesylated version of pre-lamin A called progerin which
accumulates on the nuclear membrane and leads to abnormal nuclear envelope shape. The primary pathology
of HGPS is atherosclerosis – a buildup of plaque within arteries – leading to stroke and death. Given this
pathology, this project aims to investigate the effects of HGPS on the endothelium that lines arteries, and the
potential of genome-editing technology to correct its vascular pathology. Little is known about the effects of
HGPS on endothelial cells (ECs) that line the arterial lumen. ECs are sensitive to shear stress exerted on them
by the flow of blood, and their gene expression is altered under different levels of shear stress. Additionally
endothelial dysfunction is a notable early event in general atherosclerosis. Examining the molecular changes
that occur in ECs in the context of HGPS is important to fully understand the disease mechanism. As a result,
Aim 1 of this project examines gene expression of HGPS ECs upon exposure to laminar shear stress. ECs
derived from iPSCs of HGPS and healthy donors will be exposed to physiologically relevant shear stress using
parallel-plate flow chambers for 24 hrs. RNA-seq will be performed to assess differences in gene expression
between ECs in static and flow conditions, and between HGPS and healthy ECs under flow. These
experiments will give insight into molecular dysfunction of HGPS ECs, leading to the development of
atherosclerosis. Because HGPS is a single gene disorder, gene editing presents as a plausible course of
treatment. The Lamin A protein is dispensable in mice, and CRISPR/Cas9 editing of LMNA to prevent Lamin
A/progerin transcription while preserving Lamin C has recently been shown to decrease progerin and slightly
increase life span in mouse models of HGPS. However, these models do not fully recapitulate human disease
phenotypes with regards to vascular pathology. It is important therefore to illustrate whether a full knockout of
Lamin A is tolerable in a humanized system. Therefore in Aim 2, the efficacy of CRISPR/Cas9 gene editing on
human cells for the treatment of HGPS will be tested. Tissue-engineered blood vessels will be constructed
using iPS-derived smooth muscle cells and ECs, and CRISPR/Cas9 machinery will be added to the perfusion
media. Aim 3 of this project will then elucidate changes in gene function after HGPS treatment in ECs. RNA-
seq will be performed on HGPS ECs that were treated with CRISPR/Cas9 targeting Lamin A transcription, then
exposed to flow as in Aim 1. This will give insight into how HGPS treatment corrects EC resp...

## Key facts

- **NIH application ID:** 10458697
- **Project number:** 5F31HL152651-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Crystal Kennedy
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458697

## Citation

> US National Institutes of Health, RePORTER application 10458697, Progeria and Vasculature: Investigating Genetic Effects and the Potential of Genome Editing for Treatment (5F31HL152651-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10458697. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*