Adele Moatti, PhD, Assistant Professor, University of Pittsburgh

A major barrier in inner ear therapeutics is not a single limitation, but a broken pipeline—where clinically relevant models, targeting strategies, and delivery mechanisms fail to align. Here, we rebuild this pipeline by integrating complementary translational advances. We establish a porcine model of cochlear synaptopathy that captures key features of human pathology, enabling meaningful evaluation of therapeutic interventions. In parallel, we generate a comprehensive map of AAV expression in the pig inner ear, providing a critical bridge between mouse studies and clinically relevant gene therapy design. We further demonstrate that extracellular vesicles (EVs) can be harnessed to enhance intratympanic AAV delivery, improving transduction efficiency while reducing immune responses. Finally, we uncover an unexpected biological lever of drug delivery: sensory-driven formulation effects. We show that modulation of taste receptor signaling can extend drug retention within the inner ear, revealing a new axis for therapeutic control. Together, these advances shift the paradigm from isolated solutions to an integrated, translatable framework for inner ear gene and drug therapies.

Lingyan Shi, PhD, Associate Professor, University of San Diego

The Shi group is developing and applying laser scanning multimodal microscopy and spectroscopic technologies -- this includes stimulated Raman scattering (SRS) spectroscopy, multiphoton fluorescence microscopy (MPF), and second harmonic generation (SHG) for studying metabolic dynamics during aging and diseases. The imaging platform is used to map in situ cellular metabolic activities and visualize the spatial distribution of newly synthesized molecules such as protein, lipid, DNA/RNA, and carbohydrates, which is important for studying aging processes, immunosenescence, as well as diseases including neuronal degeneration, diabetes, and cancer. The Shi group is integrating biorthogonal labeled SRS microscopy the multimodal microscopy, which can automatically image co-registered SRS/MPF/SHG/DO-SRS for directly imaging complex molecular events in various tissues at sub-cellular scale. These approaches represent powerful tools for disease detection, diagnosis, and treatment, as well as for mechanistic understanding of scientific fundamentals.

Jonathan Bird, PhD, University of Florida

Myosin motors sculpt the hair cell cytoskeleton to build sound sensitive stereocilia in the inner ear. We show how phase separation regulates myosin activity and produces emergent mechanical behaviors in developing hair cells.

Benjamin Perrin, PhD, School of Science, Indianapolis

Mature stereocilia contain a core of long, linear actin filaments that are tightly bundled to form a stable scaffold. In recent work, we demonstrated that short actin filaments also play a role in normal stereocilia widening, both at the tip and along the shaft. The abundance of these short filaments depends on class III myosins, MYO3A and MYO3B, but how these myosins influence stereocilia widening or how the short filaments are generated remained unclear. Our unpublished studies revealed that loss of MYO3A produces longer, thinner stereocilia, whereas simultaneous deletion of MYO3A and MYO3B at stereocilia tips leads to pronounced tapering of the tip region. These findings suggest that the myosins preserve short actin filaments around the periphery of the core, preventing them from adding onto the ends of existing filaments and thereby limiting stereocilia elongation. We hypothesized that tip filaments are nucleated by formins, proteins known to generate linear actin filaments. To test this, we treated explanted mouse cochleae with the formin inhibitor SMIFH2. Contrary to our expectations, SMIFH2 increased the levels of short actin filaments and triggered rapid elongation of stereocilia in the shorter rows. This effect appears to stem from the loss of ankle links, which we suggest normally act as a brake on stereocilia growth. Supporting this idea, ankle‑link components accumulate at stereocilia tips after SMIFH2 treatment, where they may facilitate elongation. Together, these results illuminate how actin assembly is coordinated at stereocilia tips to produce the mechanosensitive bundles essential for hearing.

Wade Chien, PhD, Johns Hopkins School of Medicine

Inner ear gene therapy is a rapidly growing field of research investigation. Currently, several clinical trials are ongoing to test the safety and efficacy of inner ear gene therapy for a specific form of hereditary hearing loss. In this talk, we will discuss the progress that has been made in the field of inner ear gene therapy. We will also address several challenges that still remain in order to translate inner ear gene therapy as an effective treatment for other types of hearing loss.

Bahareh Ajami, PhD, Oregon Health & Science University

The cochlea was long considered immune-privileged, but recent evidence reveals a complex landscape of resident immune cells whose roles in hearing remain poorly understood. Using cutting-edge single-cell RNA sequencing, fate-mapping, and functional approaches, we have identified five distinct myeloid cell populations in the mouse cochlea, including three macrophage subsets conserved in humans. Our comprehensive analysis reveals that these populations have diverse developmental origins—some derived from yolk sac precursors during embryogenesis, others continuously replenished by circulating monocytes in specific cochlear compartments. Strikingly, each population exhibits unique transcriptional signatures and spatial distributions that correlate with specialized functions. Through selective depletion studies, we demonstrate that specific macrophage subsets are critical for inner hair cell synapse formation and hearing, while others accumulate during age-related hearing loss. This work fundamentally reframes our understanding of cochlear immunology, revealing previously unappreciated cellular diversity that may represent new therapeutic targets for hearing disorders. The findings challenge the immune privilege paradigm and establish a foundation for precision approaches to treating hearing loss.   

Stéphane F. Maison, PhD, CCC-A, Massachusetts Eye and Ear and Harvard Medical School

This presentation will review how Hidden Hearing Loss was discovered, some of the methods used to measure it in humans, emerging strategies that may reverse or mitigate it, and the implications of such discovery for clinical practice in audiology and otology.

Tobias Moser, MD, University Medical Center Göttingen

When hearing fails, cochlear implants (CIs) provide open speech perception to most of the currently more than a million CI users. CIs bypass the defective sensory organ and stimulate the auditory nerve electrically. The major bottleneck of current CIs is the poor coding of spectral information, which results from wide current spread from each electrode contact. As light can be more conveniently confined, optical stimulation of the auditory nerve presents a promising perspective for a fundamental advance of CIs. Developing optogenetic stimulation for auditory research and future hearing restoration requires efforts toward development and characterization of appropriate channelrhodopsins, their viral gene transfer to cochlear neurons, as well as medical device engineering. The presentation will summarize the current state of the art and plans for developing gene therapy of the auditory nerve and optical CI as well as their combination for improved hearing restoration by optogenetic sound coding.

Guisheng Zhong, PhD, Shanghai Tech University School of Life Science and Technology, iHuman Institute

Hereditary hearing loss affects millions worldwide, with gene therapy emerging as a promising treatment. This seminar explores advances in precise gene delivery and expression control, focusing on AAV-based strategies. We highlight the development of the ARBITER workflow to engineer cochlear cells specific cis-regulatory elements, successfully restoring hearing in Slc26a5 mutant mice. Additionally, I discuss recent preclinical/clinical results in OTOF gene therapies and describe the challenge to treat GJB2 deafness patients, offering insights into overcoming challenges in treating genetic deafness.