Advances and challenges in adeno-associated viral inner-ear gene therapy for sensorineural hearing loss

Bankoti, Kamakshi; Generotti, Charles; Hwa, Tiffany Peng; Wang, Lili; O’Malley, Bert W.; Li, Daqing

doi:10.1016/j.omtm.2021.03.005

Cited by 20 publications

(14 citation statements)

References 209 publications

(211 reference statements)

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“…In addition to CIs, OCT technology could have applications in the fields of inner ear diagnostics and regenerative therapies 55 . Regenerative therapies, relying on mesenchymal stem cells and adeno-associated viral inner-ear gene transfer, may need to be injected into the scala media compartment of the cochlea 56 , 57 . To enable optogenetic stimulation in optical CIs, photosensitivity of the auditory neurons has to be induced by injection of an adeno-associated virus-mediated gene 58 .…”

Section: Discussionmentioning

confidence: 99%

An optically-guided cochlear implant sheath for real-time monitoring of electrode insertion into the human cochlea

Starovoyt

Quirk

Putzeys

et al. 2022

Sci Rep

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In cochlear implant surgery, insertion of perimodiolar electrode arrays into the scala tympani can be complicated by trauma or even accidental translocation of the electrode array within the cochlea. In patients with partial hearing loss, cochlear trauma can not only negatively affect implant performance, but also reduce residual hearing function. These events have been related to suboptimal positioning of the cochlear implant electrode array with respect to critical cochlear walls of the scala tympani (modiolar wall, osseous spiral lamina and basilar membrane). Currently, the position of the electrode array in relation to these walls cannot be assessed during the insertion and the surgeon depends on tactile feedback, which is unreliable and often comes too late. This study presents an image-guided cochlear implant device with an integrated, fiber-optic imaging probe that provides real-time feedback using optical coherence tomography during insertion into the human cochlea. This novel device enables the surgeon to accurately detect and identify the cochlear walls ahead and to adjust the insertion trajectory, avoiding collision and trauma. The functionality of this prototype has been demonstrated in a series of insertion experiments, conducted by experienced cochlear implant surgeons on fresh-frozen human cadaveric cochleae.

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Section: Discussionmentioning

confidence: 99%

An optically-guided cochlear implant sheath for real-time monitoring of electrode insertion into the human cochlea

Starovoyt

Quirk

Putzeys

et al. 2022

Sci Rep

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“…These studies essentially targeted key deafness genes small enough to be delivered with adeno-associated virus (AAV) vectors (maximum capacity of 4.7 kb for a single AAV) ( 49 , 89 , 239 – 241 ) (see Table 1 ). In recent years, new generations of AAVs with higher transduction rates for inner ear hair cells have been tested ( 139 , 141 , 146 , 240 , 242 ). Below, we detail some key attempts at cell-specific delivery for hearing and vestibular disorders.…”

Section: Rehabilitation and Treatment Strategies For Vestibular Disor...mentioning

confidence: 99%

Vestibular Deficits in Deafness: Clinical Presentation, Animal Modeling, and Treatment Solutions

2022

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The inner ear is responsible for both hearing and balance. These functions are dependent on the correct functioning of mechanosensitive hair cells, which convert sound- and motion-induced stimuli into electrical signals conveyed to the brain. During evolution of the inner ear, the major changes occurred in the hearing organ, whereas the structure of the vestibular organs remained constant in all vertebrates over the same period. Vestibular deficits are highly prevalent in humans, due to multiple intersecting causes: genetics, environmental factors, ototoxic drugs, infections and aging. Studies of deafness genes associated with balance deficits and their corresponding animal models have shed light on the development and function of these two sensory systems. Bilateral vestibular deficits often impair individual postural control, gaze stabilization, locomotion and spatial orientation. The resulting dizziness, vertigo, and/or falls (frequent in elderly populations) greatly affect patient quality of life. In the absence of treatment, prosthetic devices, such as vestibular implants, providing information about the direction, amplitude and velocity of body movements, are being developed and have given promising results in animal models and humans. Novel methods and techniques have led to major progress in gene therapies targeting the inner ear (gene supplementation and gene editing), 3D inner ear organoids and reprograming protocols for generating hair cell-like cells. These rapid advances in multiscale approaches covering basic research, clinical diagnostics and therapies are fostering interdisciplinary research to develop personalized treatments for vestibular disorders.

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“…In this context, here, we propose to develop a therapeutic approach in male Pou3f4 −/y mice based on a viral vector‐mediated gene transfer in cochlear SLFs. Adeno‐associated virus (AAV) is an effective nonpathogenic in vivo gene‐transfer vector that can be used for treating hearing loss in mouse models of human genetic deafness 113–116 . Many AAV serotypes have been engineered to improve their transduction to distinct cell types in the cochlea.…”

Section: A Gene Therapy‐based Approach To Rescue the Sensorineural Lo...mentioning

confidence: 99%

Considering gene therapy to protect from X‐linked deafness DFNX2 and associated neurodevelopmental disorders

Defourny

2022

Ibrain

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Mutations and deletions in the gene or upstream of the gene encoding the POU3F4 transcription factor cause X-linked progressive deafness DFNX2 and additional neurodevelopmental disorders in humans. Hearing loss can be purely sensorineural or mixed, that is, with both conductive and sensorineural components. Affected males show anatomical abnormalities of the inner ear, which are jointly defined as incomplete partition type III. Current approaches to improve hearing and speech skills of DFNX2 patients do not seem to be fully effective. Owing to inner ear malformations, cochlear implantation is surgically difficult and may predispose towards severe complications. Even in cases where implantation is safely performed, hearing and speech outcomes remain highly variable among patients. Mouse models for DFNX2 deafness revealed that sensorineural loss could arise from a dysfunction of spiral ligament fibrocytes in the lateral wall of the cochlea, which leads to reduced endocochlear potential. Highly positive endocochlear potential is critical for sensory hair cell mechanotransduction and hearing. In this context, here, we propose to develop a therapeutic approach in male Pou3f4 −/y mice based on an adeno-associated viral (AAV) vector-mediated gene transfer in cochlear spiral ligament fibrocytes. Among a broad range of AAV vectors, AAV7 was found to show a strong tropism for the spiral ligament. Thus, we suggest that an AAV7mediated delivery of Pou3f4 complementary DNA in the spiral ligament of Pou3f4 −/y mice could represent an attractive strategy to prevent fibrocyte degeneration and to restore normal cochlear functions and properties, including a positive endocochlear potential, before hearing loss progresses to profound deafness.

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Advances and challenges in adeno-associated viral inner-ear gene therapy for sensorineural hearing loss

Cited by 20 publications

References 209 publications

An optically-guided cochlear implant sheath for real-time monitoring of electrode insertion into the human cochlea

An optically-guided cochlear implant sheath for real-time monitoring of electrode insertion into the human cochlea

Vestibular Deficits in Deafness: Clinical Presentation, Animal Modeling, and Treatment Solutions

Considering gene therapy to protect from X‐linked deafness DFNX2 and associated neurodevelopmental disorders

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