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1.
EMBO Mol Med ; 15(10): e17393, 2023 Oct 11.
Article in English | MEDLINE | ID: mdl-37642150

ABSTRACT

Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X-linked disorder, caused by NDP gene mutation. It manifests as blindness at birth and progressive sensorineural hearing loss, leading to debilitating dual sensory deprivation. To develop a gene therapy, we used a Norrie disease mouse model (Ndptm1Wbrg ), which recapitulates abnormal retinal vascularisation and progressive hearing loss. We delivered human NDP cDNA by intravenous injection of adeno-associated viral vector (AAV)9 at neonatal, juvenile and young adult pathological stages and investigated its therapeutic effects on the retina and cochlea. Neonatal treatment prevented the death of the sensory cochlear hair cells and rescued cochlear disease biomarkers as demonstrated by RNAseq and physiological measurements of auditory function. Retinal vascularisation and electroretinograms were restored to normal by neonatal treatment. Delivery of NDP gene therapy after the onset of the degenerative inner ear disease also ameliorated the cochlear pathology, supporting the feasibility of a clinical treatment for progressive hearing loss in people with Norrie disease.

2.
Adv Exp Med Biol ; 1415: 555-563, 2023.
Article in English | MEDLINE | ID: mdl-37440086

ABSTRACT

Retinitis pigmentosa (RP) causes blindness in 1 out of 3000-4000 individuals worldwide. Understanding the disease mechanism underlying the death of photoreceptors in RP patient is crucial for the discovery and development of therapies to prevent and stop the progression of retinal degeneration. Despite having provided valuable insight into RP pathology, several shortcomings of animal models warrant the need for a better modeling system. This review discusses the current use of patient-derived induced pluripotent stem cells (iPSCs) to model RP and its advantages over animal models. Further improvement to enhance the representativeness of iPSC RP models is also discussed.


Subject(s)
Induced Pluripotent Stem Cells , Retinal Degeneration , Retinitis Pigmentosa , Animals , Induced Pluripotent Stem Cells/pathology , Retinitis Pigmentosa/therapy , Retinitis Pigmentosa/pathology , Retinal Degeneration/therapy , Photoreceptor Cells/pathology , Models, Animal , Retina/pathology
3.
Stem Cell Reports ; 17(11): 2421-2437, 2022 11 08.
Article in English | MEDLINE | ID: mdl-36240775

ABSTRACT

Usher syndrome-associated retinitis pigmentosa (RP) causes progressive retinal degeneration, which has no cure. The pathomechanism of Usher type 1B (USH1B)-RP caused by MYO7A mutation remains elusive because of the lack of faithful animal models and limited knowledge of MYO7A function. Here, we analyzed 3D retinal organoids generated from USH1B patient-derived induced pluripotent stem cells. Increased differential gene expression occurred over time without excessive photoreceptor cell death in USH1B organoids compared with controls. Dysregulated genes were enriched first for mitochondrial functions and then proteasomal ubiquitin-dependent protein catabolic processes and RNA splicing. Single-cell RNA sequencing revealed MYO7A expression in rod photoreceptor and Müller glial cells corresponding to upregulation of stress responses in NRL+ rods and apoptotic signaling pathways in VIM+ Müller cells, pointing to the defensive mechanisms that mitigate photoreceptor cell death. This first human model for USH1B-RP provides a representation of patient retina in vivo relevant for development of therapeutic strategies.


Subject(s)
Organoids , Retinitis Pigmentosa , Animals , Humans , Myosin VIIa , Organoids/pathology , Pathology, Molecular , Myosins/genetics , Myosins/metabolism , Retina/metabolism , Retinitis Pigmentosa/genetics , Retinitis Pigmentosa/pathology , Retinal Rod Photoreceptor Cells/pathology
4.
Sci Rep ; 12(1): 6646, 2022 04 22.
Article in English | MEDLINE | ID: mdl-35459774

ABSTRACT

Retinal degenerative diseases are a leading cause of blindness worldwide with debilitating life-long consequences for the affected individuals. Cell therapy is considered a potential future clinical intervention to restore and preserve sight by replacing lost photoreceptors and/or retinal pigment epithelium. Development of protocols to generate retinal tissue from human pluripotent stem cells (hPSC), reliably and at scale, can provide a platform to generate photoreceptors for cell therapy and to model retinal disease in vitro. Here, we describe an improved differentiation platform to generate retinal organoids from hPSC at scale and free from time-consuming manual microdissection steps. The scale up was achieved using an agarose mould platform enabling generation of uniform self-assembled 3D spheres from dissociated hPSC in microwells. Subsequent retinal differentiation was efficiently achieved via a stepwise differentiation protocol using a number of small molecules. To facilitate clinical translation, xeno-free approaches were developed by substituting Matrigel™ and foetal bovine serum with recombinant laminin and human platelet lysate, respectively. Generated retinal organoids exhibited important features reminiscent of retinal tissue including correct site-specific localisation of proteins involved in phototransduction.


Subject(s)
Pluripotent Stem Cells , Cell Differentiation , Humans , Organoids , Retina , Retinal Pigment Epithelium/metabolism
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