Genetically modified marmosets as a model for human deafness

"Myrabello“ is a genetically modified marmoset. The image is from a video.
Photo Credit: Katharina Diederich

Scientific Frontline: Extended "At a Glance" Summary: Genetically Modified Marmosets as a Model for Human Deafness

The Core Concept: Researchers have successfully utilized CRISPR/Cas9 technology to create genetically modified marmosets with a non-functional OTOF gene, establishing the first realistic primate model for congenital human deafness.

Key Distinction/Mechanism: Unlike previous mouse models or cell cultures, this primate model closely mirrors human hearing development and physiology. By precisely knocking out the OTOF gene, the inner ear ceases to produce the protein otoferlin. Without otoferlin, acoustic signals cannot be transmitted from the inner ear's hair cells to the auditory nerve, resulting in profound deafness despite a physically intact ear structure.

Major Frameworks/Components:

• CRISPR/Cas9 Genome Editing: Applied to precisely eliminate the OTOF gene function in fertilized marmoset eggs.
• Reproductive Biology: Involves the successful implantation of the modified embryos into surrogate mothers, resulting in healthy, normally developing offspring that are deaf from birth.
• Electrophysiological Verification: The use of EEG-like diagnostic methods to confirm deafness and cellular analysis to verify the absence of the otoferlin protein.
• Translational Pipeline: Serves as a critical bridge connecting in vitro and murine research to clinical human applications.

Branch of Science: Genetics, Molecular Biology, Auditory Neuroscience, Reproductive Biology, and Translational Medicine.

Future Application: The primate model will be utilized to test, optimize, and evaluate the long-term safety and efficacy of novel OTOF gene therapies and optogenetic cochlear implants. Furthermore, the genetic techniques established here can be adapted to develop models for other incurable genetic diseases.

Why It Matters: Defective OTOF genes are a leading cause of congenital hearing loss in humans. Having a primate model that accurately replicates this condition is a crucial milestone for the safe and targeted advancement of inner-ear therapeutics, moving medicine closer to viable cures for inherited deafness.

Photo Credit: Nancy Rüger

Why are some people unable to hear from birth, even though their inner ear appears intact? One possible cause lies in the so-called OTOF gene. It plays a central role in transmitting sound signals from the hair cells to the auditory nerve. Without this function, acoustic information does not reach the brain. Researchers from the German Primate Center – Leibniz Institute for Primate Research in close cooperation with the University Medical Center Göttingen and the Max Planck Institute for Multidisciplinary Sciences have now, for the first time, generated marmosets in which this gene has been knocked out precisely. The animals are healthy and develop normally but are deaf from birth. This provides the first primate model that realistically replicates key characteristics of human deafness. 

Hearing loss is one of the most common congenital sensory disorders in humans. A major cause is a defect in the OTOF gene. This gene ensures that the protein otoferlin is produced in the inner ear. This protein is necessary for sound signals to travel from the hair cells to the auditory nerve. Without it, the ear still functions externally, but the signals do not reach the brain. 

Genetically modified marmosets 

The Göttingen research team used the CRISPR/Cas9 gene-editing tool to modify precisely the OTOF gene in fertilized marmoset eggs, rendering it non-functional in the resulting offspring. The genetically modified embryos were then implanted into a surrogate mother. The animals that were born developed normally, but they were deaf from birth. Hearing tests using electrophysiological methods, similar to an EEG, confirmed deafness, as is also observed in patients with an OTOF gene defect. The absence of otoferlin protein in the inner hair cells further confirmed the genetic knockout. 

A crucial step toward new therapies 

“With the OTOF-knockout marmosets, we now have, for the first time, a primate model that realistically replicates human OTOF-related hearing loss,” says Tobias Moser, Director of the Institute of Auditory Neuroscience at the University Medical Center Göttingen. “This gives us a crucial tool for developing new therapies in a more targeted and safer manner, while also considering their long-term effects.” 

The new model bridges an important gap between mouse models, cell culture systems, and clinical applications. It enables studies under conditions that more closely resemble human hearing development and physiology than previous models. This is particularly significant for the further development of novel inner ear therapies. 

Complex research in interdisciplinary collaboration 

This project was made possible through close interdisciplinary collaboration between scientists at the German Primate Center, the University Medical Center Göttingen, and the Max Planck Institute for Multidisciplinary Sciences. 

“Creating genetically precisely modified primates is extraordinarily challenging from a reproductive and molecular biology perspective. The fact that we succeeded in doing this for OTOF in marmosets demonstrates what is possible when reproductive biology, genome editing, and biomedical and veterinary research collaborate closely.” 

Prof. Dr. Rüdiger Behr, Head of the Stem Cell and Regeneration Biology Unit 

Prospects for the medicine of the future 

The new model provides an important foundation for further developing gene therapies and other innovative approaches to treating hearing disorders. The goal is to better understand their safety, efficacy, and long-term stability. Furthermore, the precise genetic modification of marmosets opens up new possibilities for developing additional disease models and advancing therapies for previously incurable diseases. 

“This model represents a major step forward for translational research,” says Marcus Jeschke, professor at the German Primate Center and at the University Medical Center Göttingen. “It offers the opportunity to test and optimize OTOF gene therapies and optogenetic cochlear implants under conditions that are significantly closer to human hearing than previous models.” 

Funding: The work was funded by the Leibniz Cooperative Excellence Program, the DFG Cluster of Excellence MBExC, the DFG Collaborative Research Center 1690, and the Else Kröner Fresenius Center for Optogenetic Therapies. 

Published in journal: Nature Communications

Title: Generation of marmoset monkeys with a non-mosaic disruption of the OTOF gene as a model of human deafness

Authors: Tobias Kahland, Dimitri Leonid Lindenwald, Marcus Jeschke, Kathrin Kusch, Olena Tkachenko Eikel, Mara Uhl, Nancy Rüger, Charis Drummer, Bettina Wolf, Fritz Benseler, Nils Brose, Rüdiger Behr, and Tobias Moser

Source/Credit: Leibniz Institute for Primate Research

Reference Number: gen033126_01

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