# Nanoparticles based mRNA delivery for treatment of cystic fibrosis

> **NIH NIH R01** · OREGON STATE UNIVERSITY · 2020 · $666,748

## Abstract

ABSTRACT:
Cystic fibrosis (CF) is conferred by any of ≥1200 known mutations in the gene encoding the CFTR, an ion
transporter protein, but in principle, a single gene therapy agent that delivers expression of functional CFTR
could treat. Prior attempts to do so have used adeno-associated viral or liposomal delivery systems to deliver
CFTR DNA. Although some of these reached Phase I-IIB clinical trials, they failed to produce consistent,
impactful improvement of patient outcomes. We developed a novel lipid nanoparticle (LNP)-based system to
deliver mRNA, and found it successfully restored up to 55% of normal CFTR-mediated chloride efflux in the
nasal epithelium of CFTR-deficient mice. To exploit and apply these novel discoveries, the long-term goal of this
project is to overcome two key remaining biological barriers that limit entry of all gene therapy vectors into the
lung: 1) the thick, sticky airway/lung epithelial mucus of CF that impedes gene carriers from reaching airway
cells, and 2) inadequate cytosolic bioavailability of genetic material after uptake by cells, due to endosomal
entrapment. Overcoming these two obstacles will require opposing particle characteristics: mucosal penetration
is achievable primarily by stabilizing particles with a muco-inert polymer, whereas intracellular bioavailability of
genetic payloads relies on particle destabilization. There is urgent need to develop nanoparticles stable enough
to cross CF mucus and reach airway cells, yet labile enough to facilitate endosomal escape of genetic material
following cellular uptake. We will meet these criteria, by altering the stability of the LNP core, while maintaining
a muco-inert LNP surface. We found that replacing cholesterol with its naturally-occurring analogues improves
intracellular gene delivery by 200-fold, vs. that seen with a clinically successful cholesterol-containing LNP. We
posit that this major improvement in gene transfer occur via modifications in the enhanced LNP (eLNPs) core
structure and trafficking. Modifications in eLNPs' core structure as we propose will enable disassembly,
endosomal escape and cytosolic delivery of mRNA, while maintaining their muco-inert surface properties. Our
translational project's goal is to analyze LNP structure and intracellular trafficking within the CF lung. Our
objectives are thus 1) elucidate and optimize the structural features of nanocarriers that drive endosomal
trafficking of eLNPs and enhanced gene delivery, 2) test and optimize the ability of altered core structures to
enhance mucopenetration across human CF sputum and state of art mice models, and 3) assess safety of
sustained transmucosal transfection of CFTR mRNA via repeated aerosolization in CF rats, including
toxicological analyses. These studies will significantly advance translational therapy, enabling long-term
restoration of CFTR function to halt or reverse model CF disease progression. Our novel approach alters internal
particle stability via small stru...

## Key facts

- **NIH application ID:** 9898461
- **Project number:** 5R01HL146736-02
- **Recipient organization:** OREGON STATE UNIVERSITY
- **Principal Investigator:** Gaurav Sahay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $666,748
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898461

## Citation

> US National Institutes of Health, RePORTER application 9898461, Nanoparticles based mRNA delivery for treatment of cystic fibrosis (5R01HL146736-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898461. Licensed CC0.

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