Podcast recap: Ellen Reisinger on gene therapy for hereditary deafness

In the last episode of The Genetics Podcast, we spoke with Dr. Ellen Reisinger, Professor at the University of Tübingen. Ellen has spent nearly twenty years studying the molecular mechanisms of hearing, particularly the role of otoferlin (OTOF) in inner hair cell neurotransmission. Her early work was fully basic science, focused on gene expression during cochlear development and the fundamental biology of hair cell function.

From basic research to translational gene therapy

The transition into therapeutics happened gradually. Early gene therapy attempts for OTOF were not successful, but a new student who wanted to learn advanced cloning techniques provided the right moment to revisit the idea. Together, the team designed dual AAV vectors capable of delivering the full OTOF coding sequence to inner hair cells in mice. The experiments worked and restored hearing in mouse models, offering one of the first viable paths toward an inner-ear gene therapy that could be used postnatally in humans.

This shift from biology to therapy illustrates how progress often comes from persistent foundational work paired with the right technical opportunity. In this case, years of mechanistic research created the knowledge base needed to act when a feasible delivery system emerged.

Why OTOF was the first clinical candidate

Of the more than 150 genes linked to hereditary hearing loss, OTOF stands out for several reasons. Children with biallelic OTOF mutations are born profoundly deaf, but their outer hair cells still function. Newborn hearing screenings often miss the condition because these tests measure outer hair cell activity rather than inner hair cell neurotransmission. Parents typically notice the issue only when their child fails to respond to sound or begins to miss developmental speech milestones.

What makes OTOF particularly tractable for gene therapy is that inner hair cells and their synapses are present and structurally intact, even though they do not function properly. In mouse models, these cells remain intact for months, which implies that there is a viable postnatal therapeutic window in humans. This is very different from many degenerative forms of deafness where hair cells deteriorate early, limiting intervention options.

From a clinical risk standpoint, OTOF is also favorable because the established fallback treatment is a cochlear implant. Even if gene therapy does not work, children still have a reliable, widely used, and effective option for speech and language development. Taken together, these factors made OTOF an excellent target for inner ear gene therapy.

How dual AAV works and why it matters

AAV vectors can carry only about 3 kb of genetic material once regulatory elements are included. The OTOF coding sequence is about twice that size. Ellen’s group solved this by splitting the gene across two separate AAV vectors. When both vectors enter the same inner hair cell, their genomes naturally concatemerize inside the nucleus, forming a contiguous sequence that can be transcribed as a full-length otoferlin mRNA.

This approach had been used in the retina and muscle fields, but applying it to the inner ear required careful optimization. The inner ear’s anatomy is small and sensitive, and the delivery route must be precise. Still, the dual AAV strategy worked reliably in mice and provided a blueprint for the companies and clinical researchers now advancing OTOF gene therapy in children.

Dual AAV is likely to remain an important tool for hearing research because many relevant genes are too large for single AAV vectors. Approaches like gene editing or HITI (using CRISPR/Cas9) may eventually offer alternatives, but for now it is the method with the strongest evidence base in this setting.

What comes after OTOF

Beyond OTOF, Ellen’s view is that there is no second candidate with the same combination of preserved structure, clear pathophysiology, and postnatal treatment window for now. Many forms of hereditary deafness involve degeneration, where hair cells or auditory neurons deteriorate early in life. In those cases, treating after birth may be too late.

One of the most common genes, GJB2, is responsible for a large share of congenital hearing loss. However, several obstacles make it hard to target with gene therapy. The knockout mouse is embryonic lethal due to placental effects, so researchers rely on conditional models that do not perfectly match the human condition. Structural damage in the cochlea also appears severe in many GJB2 patients. Ellen believes gene therapy might help children who still retain some hearing at birth, but she does not expect complete restoration in those born profoundly deaf.

For rarer genes, the challenge is often finding enough patients for a trial. Even when the biology looks promising, the logistical reality can slow progress. That makes the lessons from the OTOF programs especially valuable, because they help define what clinical, anatomical, and biological characteristics support a viable postnatal treatment strategy.

Beyond single-gene therapy

While monogenic childhood deafness is still approached gene by gene, Ellen sees broader potential in age-related and noise-induced hearing loss, where shared pathways may matter more. Early work points to roles for immune response, inflammation, and endogenous protective mechanisms, with examples including estrogen-related protection in female mice and protective effects of metformin in males.

These findings are early, but they suggest that hearing loss in adulthood may eventually benefit from pathway-level therapies rather than gene-specific ones. Ellen’s lab is studying protective signaling in noise trauma models, with the hope of identifying targets that could reduce damage or enhance natural repair processes.

Comparing gene therapy with cochlear implants

A key question is how gene therapy outcomes will compare to cochlear implants over time. Implants are highly effective for speech and language development, and more than a million people worldwide use them. Their main limitation is pitch resolution, which affects music perception and tone discrimination.

Gene therapy, if successful, should support more natural pitch perception because it restores synaptic signaling. However, speech comprehension depends on the level of otoferlin expression achieved in each treated child. In mice with partial otoferlin expression, tasks analogous to human consonant recognition are impaired. In languages where consonant distinctions matter a lot, cochlear implants may perform better unless gene therapy delivers near-normal protein expression.

For tonal languages like Mandarin, gene therapy may offer clearer benefits because pitch information is essential for distinguishing syllables. Ellen expects that some families may choose one ear treated with gene therapy and the other with an implant, capturing the advantages of both approaches.

Conclusion

OTOF gene therapy advanced because the biology, animal models, and clinical conditions aligned in a way that made postnatal intervention feasible. The next targets will be harder, especially those with early degeneration or limited patient numbers. At the same time, broader work on protective pathways hints at future therapies for age-related and noise-induced hearing loss. For now, cochlear implants remain an excellent standard, while gene therapies move into clinical trials and generate the first long-term data.

A note on perspectives within the Deaf community
Not all deaf or hard-of-hearing people view deafness as something that should be medically treated. Many identify culturally with the Deaf community and do not seek interventions. This recap focuses on gene therapy research for families who pursue it, while respecting the full range of perspectives.

Listen to the full episode below.