Otoferlin is a protein that plays a role in the sense of hearing. This protein is involved in how sound information travels from the ear to the brain. Its proper function is integral for the complex process of auditory signal transmission.
Otoferlin’s Function in the Inner Ear
Otoferlin is located within the inner hair cells of the cochlea, a spiral-shaped structure in the inner ear. These inner hair cells are sensory cells that convert sound vibrations into electrical signals. Otoferlin acts as a calcium sensor within these cells, analogous to a switch or a gatekeeper. When sound vibrations enter the ear, they cause the inner hair cells to depolarize, leading to an influx of calcium ions.
Otoferlin detects this rise in intracellular calcium. This detection triggers the release of neurotransmitters, which are chemical messengers, from vesicles within the hair cell. These neurotransmitters then carry the sound signal across the synapse to the auditory nerve. From the auditory nerve, the signal travels to the brain for interpretation as sound. Without functional otoferlin, this important step in signal transmission stops, preventing the sound information from reaching the brain even if the hair cells initially detect the sound.
Hearing Loss Caused by Otoferlin Mutations
When otoferlin is faulty or absent, it leads to a condition known as OTOF-related deafness. This condition is a form of auditory neuropathy spectrum disorder (ANSD), often referred to as DFNB9. A unique characteristic of this type of hearing loss is that the inner ear structures, including the cochlea and hair cells, can still detect sound vibrations. However, the signal transmission from these hair cells to the brain is impaired due to the lack of functional otoferlin.
This means that while the ear might receive the sound, the brain does not receive a clear message, leading to profound hearing loss. Traditional hearing aids are often not effective for individuals with OTOF-related deafness. This is because hearing aids primarily amplify sound, but the problem lies in the transmission of the signal, not just the volume of the sound. Cochlear implants, which bypass the dysfunctional synapse and directly stimulate the auditory nerve, can provide benefit for these individuals.
The OTOF Gene and Diagnosis
The instructions for building the otoferlin protein are contained within the gene called OTOF. Mutations, or changes, in this OTOF gene can result in the production of a non-functional otoferlin protein, or sometimes no protein at all. The condition is congenital, meaning it is present from birth, and follows a recessive genetic inheritance pattern. This means a child must inherit a mutated copy of the OTOF gene from both parents to develop the condition.
Genetic testing is the method for diagnosing OTOF-related deafness. This testing analyzes an individual’s DNA to identify specific mutations in the OTOF gene. This diagnostic clarity is important because it differentiates OTOF-related hearing loss from other forms of deafness, guiding appropriate interventions and family planning. Genetic panels are available that can test for OTOF mutations along with other genes associated with hearing loss.
Gene Therapy as a Treatment
Gene therapy offers a promising approach for treating OTOF-related deafness by directly addressing the genetic root cause. The goal is to deliver a healthy, functional copy of the OTOF gene to the inner hair cells within the cochlea. This aims to enable the cells to produce functional otoferlin protein, thereby restoring proper signal transmission to the brain.
A common method for delivering this healthy gene involves using a modified, harmless adeno-associated virus (AAV) as a vector to carry the OTOF gene directly into the targeted inner ear cells. The full-length OTOF gene is quite large, often exceeding the typical packaging capacity of a single AAV vector. To overcome this, a dual-AAV delivery strategy has been developed, where the OTOF gene is split into two parts and delivered by two separate AAV vectors.
Recent clinical trials have shown positive results, marking a breakthrough in treating genetic deafness. In some trials, children with OTOF-related deafness have demonstrated significant hearing recovery, with measurable improvements in auditory brainstem response (ABR) thresholds, sometimes reducing from over 95 decibels to around 52 decibels. These improvements in hearing have been accompanied by enhanced speech perception and the ability to engage in normal conversation. The gene therapy is administered via a single injection into the round window, a membrane at the base of the cochlea, and improvements can be observed within weeks. This success represents a major advance for individuals with OTOF-related hearing loss and highlights the potential of modern gene therapy in the management of hearing impairment.