The natural history, clinical outcomes, and genotype–phenotype relationship of otoferlin-related hearing loss: a systematic, quantitative literature review

Ford, Charles L.; Riggs, William J.; Quigley, Tera; Keifer, Orion P.; Whitton, Jonathon P.; Valayannopoulos, Vassili

doi:10.1007/s00439-023-02595-5

Cited by 12 publications

(2 citation statements)

References 110 publications

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“…[ 4 ] Homozygous and compound heterozygous OTOF mutations mostly cause severe to profound prelingual deafness and temperature‐sensitive deafness. [ 5 , 6 , 7 ]…”

Section: Introductionmentioning

confidence: 99%

AAV‐Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness

Qi,

Tan,

Zhang

et al. 2024

Advanced Science

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Mutations in OTOFERLIN (OTOF) lead to the autosomal recessive deafness 9 (DFNB9). The efficacy of adeno‐associated virus (AAV)‐mediated OTOF gene replacement therapy is extensively validated in Otof‐deficient mice. However, the clinical safety and efficacy of AAV‐OTOF is not reported. Here, AAV‐OTOF is generated using good manufacturing practice and validated its efficacy and safety in mouse and non‐human primates in order to determine the optimal injection dose, volume, and administration route for clinical trials. Subsequently, AAV‐OTOF is delivered into one cochlea of a 5‐year‐old deaf patient and into the bilateral cochleae of an 8‐year‐old deaf patient with OTOF mutations. Obvious hearing improvement is detected by the auditory brainstem response (ABR) and the pure‐tone audiometry (PTA) in these two patients. Hearing in the injected ear of the 5‐year‐old patient can be restored to the normal range at 1 month after AAV‐OTOF injection, while the 8‐year‐old patient can hear the conversational sounds. Most importantly, the 5‐year‐old patient can hear and recognize speech only through the AAV‐OTOF‐injected ear. This study is the first to demonstrate the safety and efficacy of AAV‐OTOF in patients, expands and optimizes current OTOF‐related gene therapy and provides valuable information for further application of gene therapies for deafness.

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“…[ 4 ] Homozygous and compound heterozygous OTOF mutations mostly cause severe to profound prelingual deafness and temperature‐sensitive deafness. [ 5 , 6 , 7 ]…”

Section: Introductionmentioning

confidence: 99%

AAV‐Mediated Gene Therapy Restores Hearing in Patients with DFNB9 Deafness

Qi,

Tan,

Zhang

et al. 2024

Advanced Science

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“…The main encouraging pathway is currently gene therapy, among those targeting genetic deafness caused by otoferlin mutation, with promising results in clinical trials ( Amariutei et al, 2023 ; Ha and Avraham, 2023 ; Lv et al, 2024 ). Though otoferlin-related hearing loss is very rare, accounting for only 1–8% of cases of hereditary deafness ( Ford et al, 2023 ), the results offer hope for treating other genetic forms of deafness. These encouraging results could spur pharmaceutical investment in this extremely underserved market.…”

Section: Introductionmentioning

confidence: 99%

Ototoxicity: a high risk to auditory function that needs to be monitored in drug development

Pasdelou,

Byelyayeva,

Malmström

et al. 2024

Front. Mol. Neurosci.

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Hearing loss constitutes a major global health concern impacting approximately 1.5 billion people worldwide. Its incidence is undergoing a substantial surge with some projecting that by 2050, a quarter of the global population will experience varying degrees of hearing deficiency. Environmental factors such as aging, exposure to loud noise, and the intake of ototoxic medications are implicated in the onset of acquired hearing loss. Ototoxicity resulting in inner ear damage is a leading cause of acquired hearing loss worldwide. This could be minimized or avoided by early testing of hearing functions in the preclinical phase of drug development. While the assessment of ototoxicity is well defined for drug candidates in the hearing field – required for drugs that are administered by the otic route and expected to reach the middle or inner ear during clinical use – ototoxicity testing is not required for all other therapeutic areas. Unfortunately, this has resulted in more than 200 ototoxic marketed medications. The aim of this publication is to raise awareness of drug-induced ototoxicity and to formulate some recommendations based on available guidelines and own experience. Ototoxicity testing programs should be adapted to the type of therapy, its indication (targeting the ear or part of other medications classes being potentially ototoxic), and the number of assets to test. For multiple molecules and/or multiple doses, screening options are available: in vitro (otic cell assays), ex vivo (cochlear explant), and in vivo (in zebrafish). In assessing the ototoxicity of a candidate drug, it is good practice to compare its ototoxicity to that of a well-known control drug of a similar class. Screening assays provide a streamlined and rapid method to know whether a drug is generally safe for inner ear structures. Mammalian animal models provide a more detailed characterization of drug ototoxicity, with a possibility to localize and quantify the damage using functional, behavioral, and morphological read-outs. Complementary histological measures are routinely conducted notably to quantify hair cells loss with cochleogram. Ototoxicity studies can be performed in rodents (mice, rats), guinea pigs and large species. However, in undertaking, or at the very least attempting, all preclinical investigations within the same species, is crucial. This encompasses starting with pharmacokinetics and pharmacology efficacy studies and extending through to toxicity studies. In life read-outs include Auditory Brainstem Response (ABR) and Distortion Product OtoAcoustic Emissions (DPOAE) measurements that assess the activity and integrity of sensory cells and the auditory nerve, reflecting sensorineural hearing loss. Accurate, reproducible, and high throughput ABR measures are fundamental to the quality and success of these preclinical trials. As in humans, in vivo otoscopic evaluations are routinely carried out to observe the tympanic membrane and auditory canal. This is often done to detect signs of inflammation. The cochlea is a tonotopic structure. Hair cell responsiveness is position and frequency dependent, with hair cells located close to the cochlea apex transducing low frequencies and those at the base transducing high frequencies. The cochleogram aims to quantify hair cells all along the cochlea and consequently determine hair cell loss related to specific frequencies. This measure is then correlated with the ABR & DPOAE results. Ototoxicity assessments evaluate the impact of drug candidates on the auditory and vestibular systems, de-risk hearing loss and balance disorders, define a safe dose, and optimize therapeutic benefits. These types of studies can be initiated during early development of a therapeutic solution, with ABR and otoscopic evaluations. Depending on the mechanism of action of the compound, studies can include DPOAE and cochleogram. Later in the development, a GLP (Good Laboratory Practice) ototoxicity study may be required based on otic related route of administration, target, or known potential otic toxicity.

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