Hearing loss affects millions of people worldwide, including one in 500 newborns and nearly half of adults over age 65. Although many cases are genetic, most hereditary forms of hearing loss have long been considered irreversible.
Now, new research from the University of Miami Miller School of Medicine and international collaborators has identified a genetic form of deafness that could be treatable—offering a potential shift in how scientists approach inherited hearing disorders.
Discovery of CPD Mutations
The study, published in the Journal of Clinical Investigation, was led by Mustafa Tekin, M.D., professor and chair of the Dr. John T. Macdonald Foundation Department of Human Genetics at the University of Miami Miller School of Medicine.
The research team identified rare mutations in the gene encoding carboxypeptidase D (CPD) in individuals from three unrelated families with congenital or early-onset deafness.
These mutations disrupt the enzyme’s ability to process arginine, a key amino acid required to produce nitric oxide—a molecule vital to the survival and function of cochlear cells. Without sufficient nitric oxide, cochlear cells experience oxidative stress and eventual cell death, leading to hearing impairment.
Analysis of population-level data, including the 100,000 Genomes Project, showed that these CPD variants occur more frequently in individuals with hearing loss than in the general population.
Multi-Layered Research Approach
The researchers used a comprehensive approach to demonstrate how CPD mutations cause hearing loss and to explore potential ways to mitigate their effects.
- Genetic analysis: Genome and exome sequencing identified CPD mutations in affected families, while larger population analyses confirmed their association with hearing loss.
- Cellular studies: Patient-derived fibroblasts showed reduced levels of arginine, nitric oxide, and cyclic guanosine monophosphate (cGMP), leading to oxidative stress and cell death. Supplementation with arginine restored these levels and reduced apoptosis.
- Pre-clinical models: In mouse cochlear cultures, silencing CPD led to the death of auditory cells, which could be partially reversed by arginine treatment. Flies lacking the CPD ortholog, known as the silver gene, showed structural and functional hearing deficits and abnormal movement. Feeding these flies arginine or sildenafil, a cGMP-enhancing drug, improved both sensory and motor functions.
Together, the findings indicate that CPD plays a crucial role in auditory cell metabolism and that restoring this disrupted pathway can help preserve hearing function.
Implications for Treatment
The results are significant because they challenge the long-held view that genetic hearing loss cannot be reversed. The study suggests that relatively simple interventions—such as arginine supplementation or medications that enhance cGMP signaling—may correct the biochemical imbalances caused by CPD deficiency.
“These findings open new therapeutic possibilities for individuals with hereditary hearing loss linked to CPD mutations,” the authors wrote.
“By restoring nitric oxide and cGMP levels, it may be possible to prevent or even reverse the progression of hearing damage.”
A Path Toward Non-Invasive Therapies
While hearing aids and cochlear implants have provided meaningful benefits to millions, they do not address the biological causes of most forms of hearing loss. The identification of CPD as a treatable genetic target represents a rare example in which a metabolic intervention—rather than gene replacement or surgery—might restore auditory function.
Dr. Tekin and his team emphasized the importance of genetic testing in identifying individuals who could benefit from metabolic or pharmacological treatments.
“This research highlights how genetics, biochemistry, and translational science can converge to reveal not only the causes of disease but also realistic opportunities for intervention”
Next Steps and Clinical Potential
Before these findings can be translated into clinical care, further research is required to determine the safety, dosage, and long-term outcomes of arginine and related compounds in patients with CPD mutations. Future work will likely include expanded animal studies and early-phase human trials.
If validated in clinical settings, therapies targeting the CPD–arginine–nitric oxide pathway could provide the first pharmacological treatment for a genetic form of hearing loss—offering new hope for patients and families affected by hereditary deafness.
The University of Miami study represents a milestone in understanding the metabolic foundations of hearing and demonstrates how uncovering a single gene’s function can lead to potentially transformative advances in care.
Reference:
Ramzan M., Ortiz-Vega N., Zafeer M.F. et al. Carboxypeptidase D deficiency causes hearing loss amenable to treatment. Journal of Clinical Investigation (2025).
