# Generation of human inner ear organoids via genetic programming

> **NIH NIH R21** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $125,424

## Abstract

PROJECT ABSTRACT
Hearing loss and balance disorders are the two most prevalent disabilities. Over 6% of people worldwide suffer
from disabling hearing loss, and over 6% suffer from balance disorders. The cells responsible for sound and
motion detections are the mechanosensory hair cells residing in the inner ear. As the degeneration of the hair
cells is irreversible in mammals, there is currently no approved medications for sensory recovery. In recent
years, derivation methods have been developed to generate inner ear cells from non-otic cells in vitro via
stepwise morphogen treatment or forced activation of hair cell transcription factors (TFs). Despite providing
unprecedented research opportunities, none of these current in vitro derivation approaches are suitable for
high-throughput therapeutic discoveries due to limitations such as being difficult to scale up and relatively
inefficient, or the lack of a spatially organized sensory epithelial structure. To overcome these limitations, this
study aims to build a novel human inner ear organoid model by genetically converting aggregated human
pluripotent stem cells (PSCs) into otic progenitor cells through CRISPR-based activation of otic progenitor TFs,
followed by self-organized cellular maturation in 3D culture. A CRISPR screen will be performed to identify
additional TFs that can enhance the lineage conversion efficiency. As only a single treatment step is required
and the derivation protocol is otic lineage-focused, this new organoid model is expected to be more scalable
and efficient than current stepwise morphogen treatment organoid models. Furthermore, as otic progenitors
have been shown to be capable of autonomously generating properly organized sensory epithelium cell types
in vitro, this novel organoid model is expected to harbor hair cells and supporting cells in a spatially organized
manner, therefore better recapitulating the native sensory epithelium structures than the existing direct hair cell
conversion models. Due to these advantages, this novel organoid model could potentially serve as a
therapeutic discovery platform for screening compounds and testing gene therapy treatments for hearing loss
and balance dysfunctions. In addition to establishing the new model, this study will investigate the underlying
mechanism of otic differentiation by identifying the direct and indirect downstream genes of a subset of otic
progenitor TFs. The identification of the transcription network that regulates the cellular identity transition from
the otic progenitors towards mature sensory cell types will significantly advance our understanding of human
inner ear development. Collectively, the proposed research will provide novel tools and insights in basic and
translational inner ear research.

## Key facts

- **NIH application ID:** 10425588
- **Project number:** 1R21DC020160-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Jing Nie
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $125,424
- **Award type:** 1
- **Project period:** 2022-04-01 → 2022-07-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10425588

## Citation

> US National Institutes of Health, RePORTER application 10425588, Generation of human inner ear organoids via genetic programming (1R21DC020160-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10425588. Licensed CC0.

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