Recent advances and future challenges in gene therapy for hearing loss

Amariutei, Ana E.; Jeng, Jing‐Yi; Safieddine, Saaïd; Marcotti, Walter

doi:10.1098/rsos.230644

Cited by 8 publications

(4 citation statements)

References 54 publications

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“…Insights from ongoing clinical trials centered on eye treatments have indicated that viral gene therapy might induce an adaptive immune response. This observation raises optimism for similar prospects in the inner ear domain [9,120,121].…”

Section: Implications Of the Immune Responsementioning

confidence: 88%

“…While the potential application of these therapeutic strategies to humans is now within closer reach than ever, substantial challenges remain on the horizon. These include optimizing the treatment's transduction efficiency and specificity through more targeted capsids and promoters, identifying superior delivery methods, and a deeper comprehension of potential treatment side effects [9,10].…”

Section: Introductionmentioning

confidence: 99%

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Gene Therapy for Inherited Hearing Loss: Updates and Remaining Challenges

Hahn,

Avraham

2023

Audiology Research

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Hearing loss stands as the most prevalent sensory deficit among humans, posing a significant global health challenge. Projections indicate that by 2050, approximately 10% of the world’s population will grapple with disabling hearing impairment. While approximately half of congenital hearing loss cases have a genetic etiology, traditional interventions such as hearing aids and cochlear implants do not completely restore normal hearing. The absence of biological treatment has prompted significant efforts in recent years, with a strong focus on gene therapy to address hereditary hearing loss. Although several studies have exhibited promising recovery from common forms of genetic deafness in mouse models, existing challenges must be overcome to make gene therapy applicable in the near future. Herein, we summarize the primary gene therapy strategies employed over past years, provide an overview of the recent achievements in preclinical studies for genetic hearing loss, and outline the current key obstacles to cochlear gene therapy.

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Section: Implications Of the Immune Responsementioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Gene Therapy for Inherited Hearing Loss: Updates and Remaining Challenges

Hahn,

Avraham

2023

Audiology Research

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“…Molecular therapies such as gene replacement, gene suppression, antisense oligonucleotides, RNA interference, and CRISPR-based gene editing [59][60][61][62], as well as precise delivery methods, techniques, and viral vectors employed for inner ear gene therapy are actively under investigation [63][64][65][66][67]. Gene therapy for HL is actively growing, and exciting new genetherapy-based strategies to restore and prevent SNHL are arising [59] with proof-of-principle studies demonstrating the therapeutic potential of molecular agents delivered to the inner ear to treat or ameliorate different types of SNHL [68,69]. These advancements are rapidly paving the way for basic science research discoveries to transition to clinical trials, with genetic testing being foundational for the development of novel personalized therapeutic options.…”

Section: Individualized Prevention and Treatment For Snhlmentioning

confidence: 99%

Hearing Loss: Genetic Testing, Current Advances and the Situation in Latin America

De Rosa,

Bernardi,

Kleppe

et al. 2024

Genes

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Congenital hearing loss is the most common birth defect, estimated to affect 2–3 in every 1000 births, with ~50–60% of those related to genetic causes. Technological advances enabled the identification of hundreds of genes related to hearing loss (HL), with important implications for patients, their families, and the community. Despite these advances, in Latin America, the population with hearing loss remains underdiagnosed, with most studies focusing on a single locus encompassing the GJB2/GJB6 genes. Here we discuss how current and emerging genetic knowledge has the potential to alter the approach to diagnosis and management of hearing loss, which is the current situation in Latin America, and the barriers that still need to be overcome.

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“…Unfortunately, several failures of drug candidates in clinical phase have dampened the interest of pharmaceutical companies in the field. 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.…”

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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Recent advances and future challenges in gene therapy for hearing loss

Cited by 8 publications

References 54 publications

Gene Therapy for Inherited Hearing Loss: Updates and Remaining Challenges

Gene Therapy for Inherited Hearing Loss: Updates and Remaining Challenges

Hearing Loss: Genetic Testing, Current Advances and the Situation in Latin America

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

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