DJ, Turn That Bass Up!: How Molecular Research and Gene Editing Are Redefining Hearing Loss and Paving the Way For a Cure

    Each week in our Neuro Seminar at Loyola we hear from guest scientists who present their research and explain how it fits into the bigger picture of neuroscience today. These talks are meant to expose us to new ideas and help us think about our own paths in science. One presentation that really caught my attention was a talk on the biochemistry of hearing by Dr. Wei-Ming Yu, DVM, PhD, which highlighted the critical role of the tectorial membrane (TM) in cochlear function. After reviewing the scientific article provided by Dr. Yu, titled “Critical role of hepsin/TMPRSS1 in hearing and tectorial membrane morphogenesis” and attending his captivating presentation I was reminded of another laboratory method I had previously studied and performed in a genetics course: using CRISPR/Cas9 gene editing to correct genetic hearing loss in mice. 

    To provide some necessary background information, Dr. Yu’s article on hepsin provides a clear example of how a single molecular player can determine whether the ear develops normally or not. In the article “Critical role of hepsin/TMPRSS1 in hearing and tectorial membrane morphogenesis” (Yang et al., 2024), the researchers explored how the enzyme hepsin affects both hearing ability and the development of the tectorial membrane. They studied the effects through knockout mice that lacked the protein “hepsin”. They found that these animals experienced severe hearing loss and clear defects in tectorial membrane structure, such as swelling, separation, and detachment from the spiral limbus. To test whether restoring hepsin could reverse these problems, the team introduced human hepsin into the knockout mice. Interestingly, only the mice that expressed functional hepsin showed partial recovery in hearing and a more compact tectorial membrane. In contrast, mice with low-expression or protease-dead hepsin didn’t improve, which shows that the enzyme’s activity is key. The authors also noticed that knockout mice had lower levels of alpha and beta tectorin proteins, which are important components that indicates the development of the tectorial membrane. These proteins were partially restored when functional hepsin was reintroduced. Thus, suggesting that hepsin helps process tectorins so they can properly integrate into the TM. Overall, the study draws the conclusion that hepsin is an essential player in normal hearing and tectorial membrane development.   

 

    While the study provided Dr. Yu focused more on the protease activity and protein processing, I found a research article from 2017 which reported that scientists successfully restored partial hearing in mice by using CRISPR to disrupt a defective copy of the TMC1 gene. This gene is known to cause progressive hereditary deafness in humans. The research team focused on a dominant mutation known as the “Beethoven” (Bth) allele, which causes gradual hair cell degeneration and hearing loss. Because dominant mutations produce disease even when only one copy of the gene is faulty, the scientists used CRISPR to selectively disrupt the mutant TMC1 allele while leaving the normal gene intact. To achieve this, the researchers packaged the Cas9 protein and its guide RNA into lipid nanoparticles and injected the complex directly into the cochlea of newborn mice. By delivering the CRISPR tactic as a protein complex instead of DNA, they were able to minimized collateral effects and limited how long Cas9 remained active in the cells. The results of this study were remarkable. They found that treated mice retained more inner ear hair cells, showed stronger acoustic startle reflexes. Not only that, but the mice had significantly lower auditory brainstem response thresholds compared to untreated controls. In other words, their hearing improved measurably. However, the intervention was partial and temporary. Some hearing loss returned after several weeks, likely because not all hair cells were successfully edited. Despite these limitations, the study marked the first experimental model that genome editing could directly target and modify disease genes inside the inner ear, offering a potential path toward genetic therapies for inherited deafness. 

    Both studies highlight different but corresponding ways that molecular interventions can restore hearing. The hepsin article focuses on protein processing and matrix assembly in the inner ear, showing that correcting developmental defects at the protein level can partially rescue hearing. The CRISPR study instead operates at the DNA level, repairing or silencing disease-causing alleles to protect hair cells. Together, these findings point toward a future in which hearing loss could be addressed at multiple levels. Techniques such as upstream genetic editing which involves using genome editing tools, particularly CRISPR-Cas9, to modify the regulatory regions upstream of a gene. The articles show we can use this technique to fix or silence mutations like TMC1, TMPRSS3, or TECTA. Or another method explored by Dr. Yu known as downstream protein rescue. This method incorporates the recovery of a purified, active protein after a separation process refer to restore function to a mutant protein, as seen by boosting or replacing enzymes like hepsin that are essential for extracellular matrix assembly. 

    

    I am a senior majoring in Biology on the Pre-Med track. Throughout my course work I have taken a number of Neuroscience and Genetics class so I find the intersection between these studies fascinating. The hepsin research we discussed in class emphasizes the importance of basic science in uncovering the mechanisms that make hearing possible. Meanwhile, the CRISPR breakthrough shows how quickly scientific discoveries can open up into experimental therapies. Both have taught me that restoring a sense as complex as hearing will likely require diverse strategies, from editing the genome to supporting protein networks. The broader implication is that the era of treating hearing loss at its root cause is closer than we think.

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