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- Title
From cells to cures: hiPSC-derived inner organoids and RNA therapy to resolve genetic hearing loss.
- Authors
Fousert, E.; van den Boogaard, W. M. C.; van der Valk, W. H.; Lucassen, A. W. A.; de Groot, J. C. M. J.; van Benthem, P. P. G.; Kremer, H.; de Vrieze, E.; van Wijk, E.; Locher, H.
- Abstract
Genetic hearing loss impacts millions worldwide, yet effective treatments remain unavailable, leaving patients reliant on technological aids such as hearing aids or cochlear implants. One major obstacle in therapy development is the lack of representative in vitro models of the human inner ear capable of mimicking genetic inner ear diseases and facilitating treatment validation. In this study, we present a novel approach to address this challenge. We differentiated human induced pluripotent stem cells (hiPSCs) derived from patients with genetic hearing diseases into 3D self-organizing inner ear organoids. Specifically, we focused on two genes associated with significant auditory impairments: USH2A, hereditary deaf-blindness, and COCH, implicated in late-onset genetic hearing loss, the latter presenting a window for intervention. We successfully generated disease-specific inner ear organoids by growing patient hiPSCs through precise modulation with small molecules and growth factors at distinct intervals. With immunohistochemistry we showed the presence of organ-specific cell structures within both USH2A- and COCH-inner ear organoids, including otic vesicles, hair cells and periotic mesenchymal cells. We compared the disease-specific inner ear organoids with healthy inner ear organoids through molecular and structural analyses and confirmed the presence of mutant transcripts in the patient-derived inner ear organoids. Moving beyond characterization, we demonstrate the clinical relevance of the model by countering the disease pheno-type with antisense oligonucleotides (ASOs) in vitro. ASOs can specifically target and modify RNA transcripts and slow down or halt genetic disease progression. We applied ASOs to late-stage disease-specific inner ear organoids via gymnotic delivery and observed its effect on mutant transcript expression through PCR analysis following ASO therapy. This study underscores the potential of human inner ear organoids as a platform for modelling genetic inner ear diseases and evaluating potential therapeutic interventions. Our findings offer promising avenues for increasing treatment options for individuals affected by genetic hearing loss, offering hope for improved outcomes and quality of life.
- Subjects
POLAND; TREATMENT of hearing disorders; DEAFNESS prevention; CONFERENCES &; conventions; RNA; INNER ear; STEM cells; HEARING disorders; CELLS
- Publication
Journal of Hearing Science, 2024, Vol 14, Issue 3, p106
- ISSN
2083-389X
- Publication type
Article