# Efficient in Vivo RNP-based Gene Editing in the Sensory Organ Inner Ear Using Bioreducible Lipid Nanoparticles

> **NIH NIH UG3** · MASSACHUSETTS EYE AND EAR INFIRMARY · 2020 · $782,510

## Abstract

Project Summary and Relevance
Application of genome editing based therapy requires efficient delivery of editing agents into disease-relevant
tissues and cells. Identification of novel delivery materials targeting somatic cells will greatly facilitate the
advance of editing based therapy strategies to clinic. We propose to screen a large library of novel lipid
nanoparticles for RNP (ribonucleoprotein) delivery of editing agents into the mammalian sensory organ inner
ear. Inner ear is an ideal sensory organ to develop new delivery strategies. It consists of multiple differentiated
somatic cell types without effective delivery options. Gene mutations in the major inner ear cell types have been
associated with genetic hearing loss, which affects one in 500 newborns and currently has no effective
therapies.
Lipid-based nanoparticle carriers have emerged as one of the most promising materials for delivery and have
been successfully used in clinical applications. We have developed a combinatorial library approach to
synthesize degradable lipid-like nanoparticles under reductive intracellular environments, and capable of
delivering biomolecules with high efficiency and low toxicity. The new bioreducible lipid nanoparticles
(bLNPs) have been used to deliver genome editing agents with high efficiency and low toxicity in vivo. We
have delivered genome editing RNP by cationic liposomes into mammalian inner ear in vivo, and rescued
hearing in mouse models of human genetic hearing loss. To develop editing based therapies to treat diverse
forms of genetic hearing loss, it is essential to develop a delivery strategy to target multiple inner ear cell types
simultaneously. The mammalian inner has a complicated structure with multiple cell types in small numbers,
making it particularly challenging to screen a delivery technology by conventional high-throughput strategies.
The lack of a method to detect editing at the level of the individual cell type further hinders our ability to apply
this technology in wildtype large animal models that are essential for development of this therapy for clinical
application. By combining our strategies to screen nanoparticles for delivery of editing materials to X-linked
genes in the male mouse inner ears in vivo, we will overcome these hurdles for effective delivery and editing in
diverse inner ear cell types. The study of the human inner ear tissues ex vivo will provide evidence of the
relevance of nanoparticle delivery in human disease-relevant tissues. Expansion of our work to large animal
models will be a major step towards clinical application of this technology. Our approach with nanoparticles
can be applied to the study in other organs requiring somatic cell type editing and in wildtype large animals.

## Key facts

- **NIH application ID:** 9999063
- **Project number:** 5UG3TR002636-03
- **Recipient organization:** MASSACHUSETTS EYE AND EAR INFIRMARY
- **Principal Investigator:** Zheng-Yi Chen
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $782,510
- **Award type:** 5
- **Project period:** 2018-09-18 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999063

## Citation

> US National Institutes of Health, RePORTER application 9999063, Efficient in Vivo RNP-based Gene Editing in the Sensory Organ Inner Ear Using Bioreducible Lipid Nanoparticles (5UG3TR002636-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9999063. Licensed CC0.

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