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Usher syndrome is a genetic disorder causing neurosensory hearing loss and blindness from retinitis pigmentosa (RP). Adaptive techniques such as braille, digital and optical magnifiers, mobility training, cochlear implants, or other assistive listening devices are indispensable for reducing disability. However, there is currently no treatment to re...
Contexts in source publication
Context 1
... same company that funded this study, ProQR Therapeutics, has also investigated an ASO, QR-421a, for the treatment of Usher 2A-associated RP caused by a common exon 13 mutation (c.2299delG; Van Diepen et al., 2019). The efficacy of this treatment was initially demonstrated in patient-derived retinal organoids and animal models ( Table 3), with exon-skipping capability maintained in cynomolgus monkeys for more than 100 days post-treatment. They also showed that Usherin protein was present in wild-type zebrafish larvae at the photoreceptor connecting cilium but absent in untreated c.2299delG zebrafish. ...Context 2
... gene and cell therapies pose attractive, potentially one-off solutions that would reduce the burden of invasive re-administration of medications to the eye. Though the majority of studies are currently proof-ofprinciple treatment strategies using animal models of disease (summarized in Table 3), it is highly possible that the results from current ongoing clinical trials may translate into effective new treatments (see Table 4 for a summary of ongoing clinical trials). However, more temporary therapeutics such as ASOs and translational readthrough inhibitors may also offer a significant reduction in disability. ...Citations
... Hearing aids or cochlear implants can compensate the hearing loss, but so far there is no approved causal genetic treatment for the RP in Usher syndrome. However, over the last several years research on Usher syndrome has increased, with studies on gene and cell therapies providing hope for an efficient prevention of the sensory loss (7). Nevertheless, more studies on the natural history of the disease are required to aid planning clinical trials. ...
... The scotopic and photopic full-field ERG were not recordable in both eyes in the majority of the patients (patients 3,4,5,7,8,9,10). Patient 1 showed severely reduced amplitudes in the scotopic and photopic ERG and patient 2 had reduced amplitudes in the photopic ERG and mildly reduced amplitudes in the scotopic ERG. ...
... The multifocal ERG was also not detectable. In 50% of the patients (patient 3,7,8,9,10). Patients 1, 4, 5, 6 showed reduced amplitudes in the first three inner rings and no remaining amplitudes in the two outer rings. ...
Purpose
To determine the structure of the cone photoreceptor mosaic in the macula in eyes with retinitis pigmentosa related to Usher syndrome using adaptive optics fundus (AO) imaging and to correlate these findings with those of the standard clinical diagnostics.
Methods
Ten patients with a genetically confirmed retinitis pigmentosa in Usher syndrome due to biallelic variants in MYO7A or USH2A were enrolled in the study. All patients underwent a complete ophthalmological examination including best corrected visual acuity (BCVA), spectral-domain optical coherence tomography (SD-OCT) with fundus autofluorescence photography (FAF), full-field (ffERG) and multifocal electroretinography (mfERG) and Adaptive Optics Flood Illuminated Ophthalmoscopy (AO, rtx1™, Imagine Eyes, Orsay, France). The cone density was assessed centrally and at each 0.5 degree horizontally and vertically from 1–4 degree of eccentricity.
Results
In the AO images, photoreceptor cell death was visualized as a disruption of the cone mosaic and low cone density. In the early stage of the disease, cones were still visible in the fovea, whereas outside the fovea a loss of cones was recognizable by blurry, dark patches. The blurry patches corresponded to the parafoveal hypofluorescent ring in the FAF images and the beginning loss of the IS/OS line and external limiting membrane in the SD-OCT images. FfERGs were non-recordable in 7 patients and reduced in 3. The mfERG was reduced in all patients and correlated significantly (p <0.001) with the cone density. The kinetic visual field area, measured with III4e and I4e, did not correlate with the cone density.
Conclusion
The structure of the photoreceptors in Usher syndrome patients were detectable by AO fundus imaging. The approach of using high-resolution technique to assess the photoreceptor structure complements the established clinical examinations and allows a more sensitive monitoring of early stages of retinitis pigmentosa in Usher syndrome.
... Their main advantage over AAVs is that they can be formulated to have larger carrying capacities, allowing them to carry and deliver larger genes and even proteins. Gene transfection with nanoparticles tends to be less durable than with AAV, although this may not be a disadvantage where the prolonged expression of an exogenous gene may cause unwanted effects [79]. We and others have recently reviewed how nanoparticles are formulated for various therapeutic applications to the inner ear, which we would recommend to the interested reader as that is beyond the scope of this review [57,80]. ...
Up to 1.5 billion people worldwide suffer from various forms of hearing loss, with an additional 1.1 billion people at risk from various insults such as increased consumption of recreational noise-emitting devices and ageing. The most common type of hearing impairment is sensorineural hearing loss caused by the degeneration or malfunction of cochlear hair cells or spiral ganglion nerves in the inner ear. There is currently no cure for hearing loss. However, emerging frontier technologies such as gene, drug or cell-based therapies offer hope for an effective cure. In this review, we discuss the current therapeutic progress for the treatment of hearing loss. We describe and evaluate the major therapeutic approaches being applied to hearing loss and summarize the key trials and studies.
... Among the various genetic causes of DSI, Usher syndrome is the disease that has shown the most progress in this field, as it is the most common cause, and the genes have been extensively studied [71]. Most of ongoing studies focus on gene therapy to replace the retinal degeneration that occurs in these patients [72]. However, there are also animal models in which gene therapy has been used to restore auditory and vestibular function [37,73]. ...
Purpose
This article presents a review of the main causes of inherited dual sensory impairment (DSI) with an emphasis on the multidisciplinary approach.
Methods
A narrative review of English literature published before January 2023 was conducted using PubMed, Medline, and Scopus databases. The different causes of inherited DSI are discussed from a multidisciplinary perspective.
Results
There are a wide range of dual sensory impairment (DSI), commonly referred to as blindness and deafness. While Usher syndrome is the most frequent genetic cause, other genetic syndromes such as Alport syndrome or Stickler syndrome can also lead to DSI. Various retinal phenotypes, including pigmentary retinopathy as seen in Usher syndrome, vitreoretinopathy as in Stickler syndrome, and macular dystrophy as in Alport syndrome, along with type of hearing loss (sensorineural or conductive) and additional systemic symptoms can aid in diagnostic suspicion. A thorough ophthalmologic and otorhinolaryngologic examination can help guide diagnosis, which can then be confirmed with genetic studies, crucial for determining prognosis. Effective hearing rehabilitation measures, such as hearing implants, and visual rehabilitation measures, such as low vision optical devices, are crucial for maintaining social interaction and proper development in these patients.
Conclusions
While Usher syndrome is the primary cause of inherited dual sensory impairment (DSI), other genetic syndromes can also lead to this condition. A proper diagnostic approach based on retinal phenotypes and types of hearing loss can aid in ruling out alternative causes. Multidisciplinary approaches can assist in reaching a definitive diagnosis, which has significant prognostic implications.
... To date, seven genes and three loci associated with the USH1 type have been reported, including MYO7A, USHIC, CDH23, PCDH15, USHIG, CIB2, ESPN, 21q21, 15q22-q23, and 10p11.21-q21.1, respectively (Table 1) [French et al., 2020]. USH2, the most common form, is characterized by moderate to severe congenital HL, late-onset RP (in the second decade of life), and normal vestibular function, which is the result of damaging variants in the USH2A, ADGRV1, and WHRN genes [Besnard et al., 2014;Toms et al., 2020]. ...
Introduction:
Usher syndrome (USH) is an autosomal recessive disorder that predominantly affects hearing, vision, and, in some cases, vestibular function. USH, according to the onset age, severity, and progression of symptoms, is categorized into four main types. In addition, there are a significant number of reports that patients' manifestations deviate from canonical phenotypic criteria of main types of USH, which are named atypical USH. CDH23 is the second most common USH gene in which its defects result in USH1D, non-syndromic autosomal recessive deafness-12 (DFNB12), and in a few cases, atypical USH1D. While some studies have suggested that missense and truncating damaging variants in the CDH23 gene cause DFNB12 and USH1D, respectively, no genotype-phenotype correlation for atypical USH1D has been established.
Methods:
Using whole-exome sequencing, we studied an Iranian family with two affected siblings who manifested congenital bilateral hearing loss, late-onset nyctalopia, retinitis pigmentosa, and normal vestibular function, indicating that their clinical symptoms are consistent with USH2.
Results:
Whole-exome data analysis revealed a novel bi-allelic nonsense variant (c.6562G>T; p.Glu2188Ter) in the CDH23 gene, which was confirmed by Sanger sequencing. Surprisingly, CDH23 is a member of the USH1 genes; therefore, our patients suffered from atypical USH1D. Also, by conducting a literature review, we provided a clinical and mutational profile of all reported patients with atypical manifestations or those who refuted the claimed genotype-phenotype correlation.
Conclusion:
By reporting a novel damaging variant, we expand the mutational spectrum of the CDH23 gene that leads to atypical USH1D. Also, reviewing the literature shows that, contrary to previous claims, different genotypes occur in the CDH23 gene allelic disorders, and there is no clear-cut genotype-phenotype correlation.
... Its size precludes the use of standard adeno-associated viruses (AAVs) as vectors for USH1B-targeted genetic augmentation therapy due to their relatively small cargo capacity of about 5 kb. [38][39][40] Workshop participants heard from representatives of two groups of researchers working to develop dual AAV vectors, a technology based on the inherent ability of two AAV genomes to undergo concatemerization and homologous recombination. With a dual AAV vector, the MYO7A coding sequence is divided into two pieces, and each piece is carried by one AAV. ...
Purpose:
To identify challenges and opportunities for the development of treatments for Usher syndrome (USH) type 1B.
Methods:
In September 2021, the Foundation Fighting Blindness hosted a virtual workshop of clinicians, academic and industry researchers, advocates, and affected individuals and their families to discuss the challenges and opportunities for USH1B treatment development.
Results:
The workshop began with insights from individuals affected by USH1B. Presentation topics included myosin VIIA protein function in the ear and eye and its role in disease pathology; challenges with the USH1B mouse model most used in disease research to date; new investigations into alternative disease models that may provide closer analogues to USH1B in the human retina, including retinal organoids and large animal models; and learnings from and limitations of available disease natural history data. Participants discussed the need for an open dialogue between researchers and regulators to design USH1B clinical trials with appropriate outcome measures of vision improvement, along with multimodal imaging of the retina and other testing approaches that can help inform trial designs. The workshop concluded with presentations and a roundtable reviewing emerging treatments, including USH1B-targeted genetic augmentation therapy and gene-agnostic approaches.
Conclusions:
Initiatives like this workshop are important to foster all stakeholders in support of achieving the shared goal of treating and curing USH1B.
Translational relevance:
Presentations and discussions focused on overcoming disease modeling and clinical trial design challenges to facilitate development, testing, and implementation of effective USH1B treatments.
... QR-421a is an antisense oligonucleotide that binds to a specific exon in the USH2A gene and promotes exon skipping to restore the production of functional protein. QR-421a is delivered via intravitreal injection into the eye [26]. ...
... So, it seems that the AVV vector is more suitable for the delivery of wild type MYO7A to both RPE and PRs. Besides, nanoparticle delivery of the Usher gene, thanks to their large packaging capacity, enhances the potential for Usher mutation treatment [429]. The results of animal studies finally have resulted in a phase I/II clinical trial which is currently in progress (NCT02065011), whears another clinical study has stopped not for safety reasons (NCT01505062) which was evaluating safety and tolerability of ascending doses of subretinal injections. ...
Photoreceptors (PRs), as the most abundant and light-sensing cells of the neuroretina, are responsible for converting light into electrical signals that can be interpreted by the brain. PR degeneration, including morphological and functional impairment of these cells, causes significant diminution of the retina’s ability to detect light, with consequent loss of vision. Recent findings in ocular regenerative medicine have opened promising avenues to apply neuroprotective therapy, gene therapy, cell replacement therapy, and visual prostheses to the challenge of restoring vision. However, successful visual restoration in the clinical setting requires application of these therapeutic approaches at the appropriate stage of the retinal degeneration. In this review, firstly, we discuss the mechanisms of PR degeneration by focusing on the molecular mechanisms underlying cell death. Subsequently, innovations, recent developments, and promising treatments based on the stage of disorder progression are further explored. Then, the challenges to be addressed before implementation of these therapies in clinical practice are considered. Finally, potential solutions to overcome the current limitations of this growing research area are suggested. Overall, the majority of current treatment modalities are still at an early stage of development and require extensive additional studies, both pre-clinical and clinical, before full restoration of visual function in PR degeneration diseases can be realized.
Graphical Abstract
... Proteins coded by Usher genes are usually expressed in transmembrane regions, scaffolding proteins and in motor transport. Predominantly, nonsense and splice site mutations result in syndromic conditions in affected cases [20,21]. ...
Citation: Tehreem, R.; Chen, I.; Shah, M.R.; Li, Y.; Khan, M.A.; Afshan, K.; Chen, R.; Firasat, S. Exome Sequencing Identified Molecular Determinants of Retinal Dystrophies in Nine Consanguineous Pakistani Families
Inherited retinal dystrophies (IRDs) are a heterogeneous group of degenerative disorders of the retina. Retinitis Pigmentosa (RP) is a common type of IRD that causes night blindness and loss of peripheral vision and may progress to blindness. Mutations in more than 300 genes have been associated with syndromic and non-syndromic IRDs. Recessive forms are more frequent in populations where endogamy is a social preference, such as Pakistan. The aim of this study was to identify molecular determinants of IRDs with the common presentation of night blindness in consanguineous Pakistani families. This study included nine consanguineous IRD-affected families that presented autosomal recessive inheritance of the night blindness phenotype. DNA was extracted from blood samples. Targeted exome sequencing of 344 known genes for retinal dystrophies was performed. Screening of nine affected families revealed two novel (c.5571_5576delinsCTAGATand c.471dup in EYS and SPATA7 genes, respectively) and six reported pathogenic mutations (c.304C>A, c.187C>T, c.1560C>A, c.547C>T, c.109del and c.9911_11550del in PDE6A, USH2A, USH2A, NMNAT1, PAX6 and ALMS1 genes, respectively) segregating with disease phenotype in each respective family. Molecular determinants of hereditary retinal dystrophies were identified in all screened families. Identification of novel variants aid future diagnosis of retinal dystrophies and help to provide genetic counseling to affected families.
... Proteins coded by Usher genes are usually expressed in transmembrane regions, scaffolding proteins and in motor transport. Predominantly, nonsense and splice site mutations result in syndromic conditions in affected cases [20,21]. ...
Inherited retinal dystrophies (IRDs) are a heterogeneous group of degenerative disorders of the retina. Retinitis Pigmentosa (RP) is a common type of IRD that causes night blindness and loss of peripheral vision and may progress to blindness. Mutations in more than 300 genes have been associated with syndromic and non-syndromic IRDs. Recessive forms are more frequent in populations where endogamy is a social preference, such as Pakistan. The aim of this study was to identify molecular determinants of IRDs with the common presentation of night blindness in consanguineous Pakistani families. This study included nine consanguineous IRD-affected families that presented autosomal recessive inheritance of the night blindness phenotype. DNA was extracted from blood samples. Targeted exome sequencing of 344 known genes for retinal dystrophies was performed. Screening of nine affected families revealed two novel (c.5571_5576delinsCTAGATand c.471dup in EYS and SPATA7 genes, respectively) and six reported pathogenic mutations (c.304C>A, c.187C>T, c.1560C>A, c.547C>T, c.109del and c.9911_11550del in PDE6A, USH2A, USH2A, NMNAT1, PAX6 and ALMS1 genes, respectively) segregating with disease phenotype in each respective family. Molecular determinants of hereditary retinal dystrophies were identified in all screened families. Identification of novel variants aid future diagnosis of retinal dystrophies and help to provide genetic counseling to affected families.
... Translational read-through (TR) therapy is a gene-based therapeutic approach which is able to suppress protein truncation by overreading mutations that cause premature termination of the protein translation (French et al. 2020). Small molecules, known as TR-inducing drugs (TRIDs), induce suppression of a nonsense codon by the translation machinery, resulting in elongation of the nascent peptide chain and the synthesis of full-length protein (Nagel-Wolfrum et al. 2016). ...
Usher syndrome (USH) is a rare, autosomal recessively inherited disorder resulting in a combination of sensorineural hearing loss and a progressive loss of vision resulting from retinitis pigmentosa (RP), occasionally accompanied by an altered vestibular function. More and more evidence is building up indicating that also sleep deprivation, olfactory dysfunction, deficits in tactile perception and reduced sperm motility are part of the disease etiology. USH can be clinically classified into three different types, of which Usher syndrome type 2 (USH2) is the most prevalent. In this review, we, therefore, assess the genetic and clinical aspects, available models and therapeutic developments for USH2. Mutations in USH2A, ADGRV1 and WHRN have been described to be responsible for USH2, with USH2A being the most frequently mutated USH-associated gene, explaining 50% of all cases. The proteins encoded by the USH2 genes together function in a dynamic protein complex that, among others, is found at the photoreceptor periciliary membrane and at the base of the hair bundles of inner ear hair cells. To unravel the pathogenic mechanisms underlying USH2, patient-derived cellular models and animal models including mouse, zebrafish and drosophila, have been generated that all in part mimic the USH phenotype. Multiple cellular and genetic therapeutic approaches are currently under development for USH2, mainly focused on preserving or partially restoring the visual function of which one is already in the clinical phase. These developments are opening a new gate towards a possible treatment for USH2 patients.
