Three Turkish families, no relatives, the same genetic conviction. Children are born deaf, the world remains silent. For decades, the diagnosis was a final verdict: congenital deafness neurosensory, hereditary, irreversible. Then someone looked more closely and found a gene, the CPD, which theoretically serves other purposes but has a specific role in the inner ear. When it breaks, the hair cells in the cochlea die from oxidative stress.
The reason? It's missing arginine, it's missing nitric oxide, it's missing the chemical signal that keeps alive those microscopic cells that translate sound vibrations into nerve impulses. The discovery, published on Journal of Clinical Investigation, it doesn't stop at the diagnosis. The researchers tested two therapeutic strategies.
Congenital deafness, the gene that no one was looking for
The team led by Rong Grace Zhai ofUniversity of Chicago e Mustafa Tekin ofUniversity of Miami identified rare mutations in the gene CPD (carboxypeptidase D) in five individuals from three unrelated Turkish families. All presented congenital deafness diagnosed at an early ageThe gene CPD It belongs to a family of enzymes that modify proteins by cutting their ends. It is active throughout the body, but its role in hearing was unknown.
When researchers expanded the search through the 100,000 Genomes Project British, they discovered that other people with gene mutations CPD showed signs of early hearing loss, strengthening the link between this gene and hearing function. In Italy, approximately one in 1.000 newborns is born with a form of congenital deafness, and in 60% of cases the cause is genetic.
How the mechanism works
To understand how the gene CPD affects hearing, researchers conducted experiments on mice. Normally, the gene CPD It encodes an enzyme that produces the amino acid arginine, which in turn generates nitric oxide, a neurotransmitter essential for nerve signaling. In the inner ear, gene mutations CPD interrupt this process, triggering oxidative stress and death of the delicate sensory hair cells that detect sound vibrations.
“We discovered that the CPD maintains the level of arginine in hair cells to enable a rapid signaling cascade generating nitric oxide,” Zhai explained. “That is why, although it is ubiquitously expressed in other cells of the nervous system, these hair cells in particular are more sensitive or vulnerable to the loss of CPD".
The hair cells of the cochlea are extremely delicate structures. When the gene CPD stops working, the levels of arginine, nitric oxide and cGMP (cyclic guanosine monophosphate) in the cells of patients decrease, leading to oxidative stress and cell death through endoplasmic reticulum stress-mediated mechanisms.
The silencing of the CPD in mouse cochlea cultures led to increased apoptosis.
Congenital deafness therapy that works on fruit flies
The researchers also used fruit flies as a model to study the effects of mutations CPD. The flies lacking the gene CPD They exhibited behaviors consistent with inner ear damage, such as hearing loss and balance problems. The team then tested two approaches to treat the problem: arginine supplements to compensate for that lost due to the mutation, and sildenafil (the active ingredient in Viagra), a drug that stimulates one of the pathways affected by the reduction of nitric oxide.
Both treatments They improved cell survival in patient-derived cells and reduced symptoms of hearing loss in fruit flies.Flies treated with L-arginine or sildenafil showed improved behavior, reflecting partial restoration of hearing function.
It's not the first time
This is not the first time that Gene therapy shows promising results against congenital deafness. In 2024, a little girl named Opal, born deaf due to a mutation in the gene OTOF (otoferlin), had regained his hearing thanks to an experimental therapy called DB-OTO. In that case, the treatment consisted of inserting a healthy copy of the gene into an inert virus, which was then injected into the cochlea. That mutation, like the CPD, concerns a protein involved in communication between the inner ear and the brain.
What this means for patients
“What makes this really significant is that we not only understand the underlying cellular and molecular mechanism for this type of deafness, but we have also found a promising therapeutic avenue for these patients,” Zhai said.
“This is a good example of our efforts to repurpose approved drugs FDA for the treatment of rare diseases”.
Although the study focused on individuals with a rare combination of gene mutations CPD, there could be broader implications if single mutations are linked to age-related hearing loss. The researchers plan to continue studying how nitric oxide signaling works in the inner ear sensory system and to investigate how common the mutations are. CPD in larger populations.
"How many people carry variants in this gene, and is there an age-dependent susceptibility to deafness or hearing loss?" Zhai asks. "In other words, is this a risk factor for other types of sensory neuropathy?"
The question remains open, but the discovery published on ScienceDaily represents a significant step forward in understanding the genetic basis of congenital deafness.
Unlike most genetic forms of hearing loss, which are considered irreversible, this study shows that simple interventions such as arginine supplements or drugs that enhance the signaling of the cGMP They can restore key cellular functions and reduce cell death. Genetic testing could help identify those who might benefit, paving the way for more personalized and effective treatments.
Further studies are needed, including clinical trials and larger animal studies, but the discovery of a treatable pathway for inherited hearing loss is a significant advance. For now, one question remains.
If the mutation CPD It's more common than we thought. How many people with hearing loss could benefit from a simple supplement? The answer may come soon.
