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About

Advancing Sensory Precision Medicine: From Disease Mechanisms to Therapeutic Solutions

Hearing, balance, and vision are essential for how we experience, interpret, and interact with the world. Yet, sensory impairments—often invisible and progressive—affect millions, profoundly impacting quality of life. Globally, over 460 million people live with disabling hearing loss, a figure projected to exceed one billion by 2050. Vestibular hypofunction which currently affects an estimated 403 million to 725 million people worldwide, representing 5% to 9% of the global population. In parallel, more than 285 million suffer from severe visual impairment. The economic and societal burden is immense, underscoring a critical need for transformative scientific and medical innovation.

Figure 1: The Usher syndrome sensory target organs (A,B) and structures (C). (A, B) Similarities between the eye and the inner ear. Hearing is dependent on the processing of sound waves within the hair bundle, which crown the inner (IHCs) and outer (OHCs) auditory hair cells in the cochlea (A). Light signals are transduced by the outer segments of the photoreceptors in the retina (B). In hair cells (A) and photoreceptors (B), the neurotransmitter (Glutamate) is released in synaptic active zones, where the synaptic vesicles are tethered to electron-dense structure, called ribbon. (C) The architecture of the hair bundle (wild-type) is differentially altered in absence of Usher 1 & 2 proteins.

We combine cutting-edge approaches across multiple disciplines—genetics, molecular biology, advanced imaging, electrophysiology, and behavior—to investigate the molecular, cellular, and systems-level mechanisms of hearing, balance, and vision deficits. Our multiscale and integrative phenotyping pipeline enables deep functional and structural profiling of disease models. This allows us to map disease trajectories with exceptional precision and to assess early-stage disruptions that precede irreversible damage.

At the Progressive Sensory Disorders (PSD), a research unit at the Institut de l’Audition, Institut reConnect, center of the Institut Pasteur, we are committed to advancing the frontiers of sensory neuroscience and therapy. Our research addresses the complexity of disorders affecting the inner ear and retina, with a special interest to progressive conditions that often begin postnatally and worsen over time.

Figure 2: Our deep phenotyping workflow is based on multiscale and interdisciplinary investigations, ranging from transcript to whole organism’ physiology & behavior. Collectively, the gathered information enables great precision monitoring of the sensitivity of hearing (± balance/vision deficits) in selected models, both under standard or “challenged” conditions, with or without therapeutic interventions.

Our work centers on Usher syndrome, a model for progressive deaf-blindness, and expands to other causes of late-onset sensory loss, including age-related and noise-induced hearing impairments. By leveraging both murine and porcine models, we perform cross-species analyses that mirror clinical diversity in symptom onset, severity, and progression.

Three Interconnected Research Aims

We approach sensory disorders through three primary research objectives:

  1. Deciphering Disease Mechanisms—From molecular signatures to physiological and behavioral outcomes, we aim to identify the biomarkers and pathways underlying progressive sensory dysfunction. These insights support early diagnosis and targeted interventions.
  2. Investigating External Modulators—We study how aging, environmental noise, inflammation, and oxidative stress influence disease onset and progression, identifying modifiable factors that shape patient outcomes.
  3. Developing Therapeutic Solutions—Using gene supplementation, mini-genes, dual-AAV systems, and gene editing technologies (e.g., CRISPR), we design and test novel treatments. Our goal is to develop scalable, mutation-specific therapies that restore sensory function and slow or prevent degeneration.
Figure 3: Origins of sensory impairments & variabilities in patients: age of onset, severity & progression?

Our cross-disciplinary strategy enables parallel evaluation of therapies and biomarkers in diverse models and conditions—crucial for personalizing medicine and ensuring translational success.

Our team includes principal investigators, engineers, postdoctoral fellows, and students who are passionate about linking science with therapeutic innovation. We maintain an active interface with the broader scientific, clinical, and public communities.

We welcome inquiries from motivated researchers, academic and industry collaborators.

Contact: aziz.el-amraoui@pasteur.fr | PSD-PI@pasteur.fr

Below are key recent research highlights illustrating our discoveries in gene function, disease mechanisms, and therapeutic innovation for progressive hearing loss and Usher syndrome, with direct implications for diagnosis, model development, and treatment strategies.

Highlight 1: From Gene Discovery to Therapeutic Innovation in Progressive Hearing Loss

Our team, in collaboration with Mike Bowl (UCL ear Instiutute) and Barbara Vona (InnerEarLab Gottingen), identified and characterized CLRN2 (Clarin-2) as a critical gene for auditory function, demonstrating its role in maintaining stereocilia integrity and hair cell synaptic function. Loss-of-function mutations in CLRN2 lead to progressive hearing loss in mice and humans, establishing CLRN2 as a novel deafness gene (DFNB117) (EMBO Mol. Med., 2019; Hum. Genet., 2021).

Figure 4: CLRN2 as a new deafness gene in mouse and humans. (A) Lack of clarin-2 in mice lead to progressive hearing loss, resulting in reduced sound transduction followed by loss of transducing stereocilia. (B) A consanguineous family, with individuals displaying hearing loss. The CLRN2/c.494C>A mutation leads to two defective clarin-2 proteins: (C) GWAS studies using UK biobank revealed putative CLRN2 defective variants linked to adult hearing difficulties.

We developed a gene therapy strategy using AAV9-PHP.eB vectors to deliver Clrn2 into neonatal Clrn2-deficient mice. This approach durably preserved hearing across all frequencies by maintaining stereocilia structure and synaptic function up to one year post-injection (Mol. Ther., 2024). Importantly, we showed that therapeutic efficacy declines significantly when delivery occurs after postnatal day 5, pinpointing a narrow therapeutic window.

Figure 5: Preservation of hearing sensitivity and organ structure through gene therapy in a model of progressive hearing loss. Neonatal viral-mediated delivery of clarin-2 effectively (A) and durably (B) prevents hearing loss and preserves organ structure. In contrast, the delivery of mutated CLRN2 forms does not prevent hearing deficits (C). Interestingly, unlike deliveries at postnatal day 1 (P1) and P5, Clrn2 delivery at postnatal day 10 (P10) or 14 (P14) does not prevent hearing loss, indicating a limited therapeutic window (D).

Highlight 2: Rethinking Sensory Syndromes—Clarifying CIB2 and Usher Vision Loss

We redefined the role of CIB2 in hereditary hearing loss, disqualifying its previously assumed involvement in Usher syndrome. Our studies showed that CIB2 mutations cause non-syndromic hearing loss, with no vestibular or visual defects typical of Usher type 1. This finding, supported by both genetic and animal model data (EMBO Mol. Med., 2017; Clin. Genet., 2018), reshaped diagnostic criteria and improved genetic counseling protocols (Hum. Genet., 2022).

Highlight 3: Evolutionary Adaptation and Molecular Innovation in Sensory Systems

Our investigations into the evolutionary biology of sensory organs revealed how specific molecular innovations, such as those involving spectrin βV, contributed to the functional sophistication of hearing and vision in vertebrates. Spectrin βV, an unusually large cytoskeletal protein, was shown to have undergone mammal-specific positive selection (PNAS, 2017), driving its redistribution from the apical surface (in amphibians) to lateral membranes in mammalian outer hair cells—cells responsible for cochlear amplification.

We also discovered spectrin βV’s role in retinal photoreceptors, where it interacts with Usher proteins and molecular motors to support intracellular trafficking (Hum. Mol. Genet., 2013). These findings illustrate how subtle evolutionary shifts in protein localization and function can result in key sensory evolved specialisations.

Figure 6: Evolution of the inner ear (A), and adaptive changes in the distribution of spectrin βV in the hair cells (B). (A) Evolution of the inner ear: Vestibular organs, resembling ancestral fish structures, evolved to include specialized auditory components in mammals. An organ dedicated only to hearing appeared later during evolution (in amphibians), then evolved over time: one late evolutionary event is the appearance of highly specialized outer hair cells, found only in mammalian inner ears. (B) Adaptive changes in spectrin βV distribution: From apical localization in frogs to a lateral plasma membrane role in mammalian OHCs. The F-actin rich hair bundles are labelled in red.

Simultaneously, our research resolved a longstanding puzzle in Usher syndrome: why do human patients suffer from retinal degeneration while mouse models do not?

Highlight 4: Solving the Usher Vision Loss Paradox—The Role of Calyceal Processes

Why do Usher type 1 patients lose vision, while mouse models do not? We resolved this long-standing paradox by identifying calyceal processes—actin-based structures in human photoreceptors—as essential targets of USH1 proteins (J. Cell Biol., 2012). We demonstrated that calyceal processes—actin-rich structures absent in mice but present in humans and other species—are crucial for photoreceptor maintenance and are severely disrupted in Usher syndrome (J. Cell Biol., 2017). This discovery redefined the field, highlighting the need for alternative models to study Usher retinal disease and guiding new therapeutic strategies (cf. Hum. Genet., 2022).

Figure 7: USH1 proteins in the hair cells and photoreceptor cells.
(A-B) Usher proteins form molecular networks in photoreceptor cells and hair cells, linking cytoskeletal and membrane structures. The Usher proteins-mediated network take place at the inner (IS) and outer (OS) segment interface of the photoreceptor cells (A), and at the hair cells’ hair bundle (B). The two regions display ciliary (microtubule)-based structures combined with highly specialized membrane/microvilli-like (F-actin) structures (reviewed in Hum Genet 2022). (C-D) Defects in calyceal processes disrupt outer segment morphology, causing Usher-related retinopathy.

Former Members

2000
2000
Name
Position
2015
2020
Matteo Cortese
PhD Student
2015
2020
Chiara Benedetto
Research Engineer
2020
2020
Ana Mesic
Master Student
2021
2021
Apolline Pierre
Master Student
2020
2021
Nawal Yahiaoui
Master Student (ENS)
2021
2021
Cyrielle Mohamed Kassime
Master Student
2020
2021
Maria Poter
Master Student (Erasmus, UK)
2016
2021
Pranav Patni
Ph D Student and Post-doc

Courses

Pasteur Course Hearing: from mechanisms to restoration technologies (HeaR)

This two-week course is designed for Master’s students, international PhD candidates, medical doctors, and hearing professionals seeking to deepen their understanding of recent breakthroughs in auditory system research. Through an immersive experience in modern […]

2025-10-20 09:00:00 2025-10-31 18:00:00 Europe/Paris Pasteur Course Hearing: from mechanisms to restoration technologies (HeaR) This two-week course is designed for Master’s students, international PhD candidates, medical doctors, and hearing professionals seeking to deepen their understanding of recent breakthroughs in auditory system research. Through an immersive experience in modern […] Institut de l'Audition, Rue de Charenton, Paris, France

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Annoucement : OMI Pasteur 2021 Course

We are pleased to announce the OMI Pasteur 2022 course “Neurological and sensory disorders: genes, pathogenesis & innovative therapies”, which will be held in Salzburg on March 13-19, 2022.

This OMI Pasteur course aims to promote an international exchange on fundamental and medical knowledge and advancements in the field of sensorineural degenerative disorders:

– How our brain and sensory organs work, what happens when either system fails

– Impact of ageing and external factors on our senses and cognition

– Conventional and innovative therapies to the sensory and neurological disorders

For further informations :

[gview file=”https://research.pasteur.fr/wp-content/uploads/2015/07/research_pasteur-enprogressive-sensory-disorders-pathophysiology-and-therapyfrdeficits-sensoriels-progressifs-pathophysiologie-et-therapie-omi-neurological-and-sensory-desorders-web-1.pdf”]

Contact

Phone: 33 1 76 53 50 64 Email: aziz.el-amraoui@pasteur.fr Address 63 Rue de Charenton, 75012, Paris France