Genetic Medicine for Hearing Loss: OTOF as Exemplar.

Millions of people worldwide have disabling hearing loss because one of their genes generates an incorrect version of some specific protein the ear requires for hearing. In many of these cases, delivering the correct version of the gene to a specific target cell within the inner ear has the potential to restore cochlear function to enable high-acuity physiologic hearing. Purpose: In this review, we outline our strategy for the development of genetic medicines with the potential to treat hearing loss.

Choice of vector and surgical approach enables efficient cochlear gene transfer in nonhuman primate.

Inner ear gene therapy using adeno-associated viral vectors (AAV) promises to alleviate hearing and balance disorders. We previously established the benefits of Anc80L65 in targeting inner and outer hair cells in newborn mice. To accelerate translation to humans, we now report the feasibility and efficiency of the surgical approach and vector delivery in a nonhuman primate model.

The use of nonhuman primates in studies of noise injury and treatment.

Exposure to prolonged or high intensity noise increases the risk for permanent hearing impairment. Over several decades, researchers characterized the nature of harmful noise exposures and worked to establish guidelines for effective protection. Recent laboratory studies, primarily conducted in rodent models, indicate that the auditory system may be more vulnerable to noise-induced hearing loss (NIHL) than previously thought, driving renewed inquiries into the harmful effects of noise in humans.

Morphological Immaturity of the Neonatal Organ of Corti and Associated Structures in Humans.

Although anatomical development of the cochlear duct is thought to be complete by term birth, human newborns continue to show postnatal immaturities in functional measures such as otoacoustic emissions (OAEs). Some of these OAE immaturities are no doubt influenced by incomplete maturation of the external and middle ears in infants; however, the observed prolongation of distortion-product OAE phase-gradient delays in newborns cannot readily be explained by conductive factors. This functional immaturity suggests that the human cochlea at birth may lack fully adult-like traveling-wave motion.

Effects of cochlear synaptopathy on middle-ear muscle reflexes in unanesthetized mice.

Cochlear synaptopathy, i.e. the loss of auditory-nerve connections with cochlear hair cells, is seen in aging, noise damage, and other types of acquired sensorineural hearing loss.

The middle ear muscle reflex in the diagnosis of cochlear neuropathy.

Cochlear neuropathy, i.e. the loss of auditory nerve fibers (ANFs) without loss of hair cells, may cause hearing deficits without affecting threshold sensitivity, particularly if the subset of ANFs with high thresholds and low spontaneous rates (SRs) is preferentially lost, as appears to be the case in both aging and noise-damaged cochleas.

Towards a Diagnosis of Cochlear Neuropathy with Envelope Following Responses.

Listeners with normal audiometric thresholds can still have suprathreshold deficits, for example, in the ability to discriminate sounds in complex acoustic scenes. One likely source of these deficits is cochlear neuropathy, a loss of auditory nerve (AN) fibers without hair cell damage, which can occur due to both aging and moderate acoustic overexposure. Since neuropathy can affect up to 50 % of AN fibers, its impact on suprathreshold hearing is likely profound, but progress is hindered by lack of a robust non-invasive test of neuropathy in humans.

Reliability of distortion-product otoacoustic emissions in the common marmoset (Callithrix jacchus).

This study examines the test-retest reliability of distortion-product otoacoustic emissions (DPOAEs) in ketamine-anesthetized common marmosets (Callithrix jacchus). DPOAE gain functions were measured at 16 f(2)-frequencies between 3 and 24 kHz. Test-retest reliability was assessed at the following time intervals: (1) Interleaved, in which two gain functions were obtained at each frequency before advancing to the next frequency, (2) Immediate, wherein one gain function was collected at all f(2)-frequencies and the retest was immediately performed without removing the probe tip, (3) Short-term, in which the retest followed a 10-min period with the probe removed, and (4) Long-term, wherein the retest was performed at least one week after the initial test.

Dissociation between distortion-product and click-evoked otoacoustic emissions in sheep (Ovis aries).

Distortion-product otoacoustic emissions (DPOAEs) were weak or absent in about one-third of sheep (Ovis aries) of both sexes tested for otoacoustic emissions (OAEs) even though their click-evoked OAEs (CEOAEs) seemingly were typical of other sheep of the same sex. Various pieces of evidence suggest that the absence of measurable DPOAEs was unlikely to be attributable to anesthetic effects, a poorly located probe tip, a pressure differential between middle and outer ears, season of the year, body position during testing, temperature effects, or previous medical history. Sheep apparently can exhibit a marked dissociation between DPOAEs and CEOAEs.

Effect of prenatal androgens on click-evoked otoacoustic emissions in male and female sheep (Ovis aries).

Otoacoustic emissions (OAEs) were measured in male and female Suffolk sheep (Ovis aries). Some sheep had been administered androgens or estrogens during prenatal development, some were gonadectomized after birth, and some were allowed to develop normally. As previously reported for spotted hyenas, gonadectomy did not alter the OAEs for either sex; accordingly, the untreated/intact and the untreated/gonadectomized animals were pooled to form the control groups.