Achromatopsia: Genetics and Gene Therapy

Michalakis, Stylianos; Gerhardt, Michael R.; Rudolph, Günther; Priglinger, Siegfried; Priglinger, Claudia

doi:10.1007/s40291-021-00565-z

Cited by 32 publications

(23 citation statements)

References 94 publications

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“…The stem cell-based therapy gained thereafter much attention though to be a promising treatment especially for patients who have already lost their foveal cones [54,55]. Nowadays, clinical trials on CNGB3 und CNGA3 gene-based therapies (MeiraGtx, STZtrial, Applied Genetics Technologies Corp) evaluating efficacy and safety are ongoing [38,56]. Nevertheless, success with either CNTF-, or gene-based therapy would require that cone photoreceptors and RPE are present and viable within the macula [1,38,56].…”

Section: Treatments In Achmmentioning

confidence: 99%

“…Nowadays, clinical trials on CNGB3 und CNGA3 gene-based therapies (MeiraGtx, STZtrial, Applied Genetics Technologies Corp) evaluating efficacy and safety are ongoing [38,56]. Nevertheless, success with either CNTF-, or gene-based therapy would require that cone photoreceptors and RPE are present and viable within the macula [1,38,56].…”

Section: Treatments In Achmmentioning

confidence: 99%

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Analysis of Suspected Achromatopsia by Multimodal Diagnostic Testing

Kugler,

Valmaggia,

Sturm

et al. 2023

Klin Monbl Augenheilkd

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Background: Achromatopsia (ACHM) as a hereditary cone disease might manifest in a stationary and progressive manner. The proper The primary aim of the study was to determine the spectrum of clinical and genetic diagnostics required to characterize the ACHM.The primary aim of the study was to determine the spectrum of clinical and genetic diagnostics required to characterize the ACHM. Methods: A retrospective analysis was performed in 8 patients from non-related families (5 ♀,3 ♂). Clinical phenotyping, supported by colour vision test, fundus photography-, autofluorescence- (FAF), infra-red- (IR), OCT imaging and electroretinography provided information on the current status and the course of the disease over the years. In addition, genetic examinations were performed with ACHM relevant testing (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H and the transcription factor ATF6). Results: All patients suffered photophobia and reduced BCVA (mean: 0.16; SD ± 0.08). Nystagmus was identified in 7subjects and in 1 patient a head-turn right helped to reduce the nystagmus amplitude. Colour vision testing confirmed complete ACHM in 7patients. Electrophysiology found severely reduced photopic- but also scotopic responses. Thinning and interruption of the inner segment ellipsoid (ISe) line within the macula but also FAF- and IR abnormalities in the fovea and/or parafovea were characteristic in all ACHM patients. Identification of pathogenic mutations in 6 patients helped to confirm the diagnosis of ACHM (3 ♀ and 3 ♂). Achromatopsia was linked to CNGA3- (2 ♀, 1 ♂) and CNGB3-variants (2 ♀, 2 ♂). The youngest patient (♀,10y) had 3 different CNGB3-variants on different alleles. In a patient (♂,29y) carrying 2 pathogenic digenic-triallelic CNGA3- and CNGB3-mutations, a severe progression of ISe discontinuity to coloboma-like macular atrophy was observed during the 12-year follow-up. One patient showed the rare ATF6 mutation, where a severe coloboma-like macular atrophy was observed on the left eye as early as at the age of three years. Conclusion: Combining multimodal ophthalmological diagnostics and molecular genetics when evaluating patients with ACHM helps in characterizing the disease and associated modifiers, and is therefore strongly recommended for such patients. Zusammenfassung Hintergrund: Achromatopsie (ACHM) als eine erbliche Zapfenerkrankung kann sich als stationäre oder als progressive Erkrankung manifestieren. Die genaue klinische und genetische Diagnostik kann eine individuelle Prognose, akkurate genetische Beratung und eine optimale Wahl von Sehhilfen erlauben. Das primäre Ziel der Studie war, das Spektrum der klinischen und genetischen Diagnostik zu ermitteln, um das Krankheitsbild der ACHM zu charakterisieren. Das primäre Ziel der Studie war, das Spektrum der klinischen und genetischen Diagnostik zu ermitteln, um das Krankheitsbild der ACHM zu charakterisieren. Das primäre Ziel der Studie war, das Spektrum der klinischen und genetischen Diagnostik zu ermitteln, um das Krankheitsbild der ACHM zu charakterisieren. Das primäre Ziel der Studie war, das Spektrum der klinischen und genetischen Diagnostik zu ermitteln, um das Krankheitsbild der ACHM zu charakterisieren. Methoden: Eine retrospective Analyse wurde bei 8 Patienten von nicht verwandten Familien (5 ♀,3 ♂) durchgeführt; das Alter war zum Zeitpunkt der Diagnosestellung: 5-56 y, Mittelwert 18.13 (SD±18.22). Die klinische Phänotypisierung, unterstützt durch Farbsehtests, Fundus Photographie, Autofluoreszenz- (FAF), infrarot- (IR), OCT- Bildgebung und Elektroretinographie lieferten Informationen über den aktuellen Status und den Verlauf der Erkrankung über Jahre. Zusätzlich wurden für ACHM relevante genetische Tests durchgeführt (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H und der transcription factor ATF6). Ergebnisse: Alle Patienten litten an Photophobie und reduzierter Sehschärfe (Mittelwert: 0.16; SD ± 0.08). Nystagmus wurde bei 7 von 8 Patienten festgestellt und bei 1 Patienten half es, mit einer Rechts-Kopfdrehung, die Nystagmus Amplitude zu verringern. Farbseh-Tests bestätigten komplette ACHM bei 7 Patienten. Bei der Elektrophysiologie wurden stark reduzierte photopische-, aber auch skotopische Antworten gefunden. Eine Ausdünnung und Unterbrechung der ISe Line innerhalb der Makula, aber auch FAF- und IR-Auffälligkeiten in der Fovea und/oder Parafovea waren charakteristisch bei allen ACHM-Patienten. Die Identifizierung von pathogenen Mutationen bei 6 Patienten halfen, die Diagnose der ACHM (3 ♀ and 3 ♂) zu bestätigen. Achromatopsie war verknüpft mit CNGA3- (2 ♀, 1 ♂) und CNGB3-Varianten (2 ♀, 2 ♂). Der jüngste Patient (♀,10y) hatte 3 verschiedene CNGB3-Varianten auf verschiedenen Allelen. Bei einem Patienten (♂,29y), der 2 pathogene digenisch-triallelische CNGA3- and CNGB3-Mutationen trug, wurde eine schwerwiegende Progression der ISe Unterbrechung zu einer Coloboma-artigen Makula-Atrophie beobachtet während der 12-Jahre follow-up-Zeit. Eine Patientin (♀,26y) zeigte eine seltene ATF6 Mutation, assoziiert mit monolateraler Coloboma-artigen Makula-Atrophie. Schlussfolgerung: Die Kombination von multimodaler ophthalmologischer Diagnostik und Molekulargenetik bei der Evaluierung von Patienten mit ACHM hilft bei der Charakterisierung der Erkrankung und deren assoziierten Modifikatoren und wird aus diesem Grund für solche Patienten empfehlenswert.

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Section: Treatments In Achmmentioning

confidence: 99%

Section: Treatments In Achmmentioning

confidence: 99%

Analysis of Suspected Achromatopsia by Multimodal Diagnostic Testing

Kugler,

Valmaggia,

Sturm

et al. 2023

Klin Monbl Augenheilkd

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“…It usually presents bilaterally, affecting all three types of cone photoreceptor cells. The disease can present as rod monochromacy, where there is a total lack of cone function or incomplete where cone function is reduced [ 25 ]. In early disease, the fundus can appear normal followed by RPE mottling and atrophy in later stages.…”

Section: Naturally Occurring Ird Nhp Modelsmentioning

confidence: 99%

Developing Non-Human Primate Models of Inherited Retinal Diseases

Seah

Goh

Chan

et al. 2022

Genes

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Inherited retinal diseases (IRDs) represent a genetically and clinically heterogenous group of diseases that can eventually lead to blindness. Advances in sequencing technologies have resulted in better molecular characterization and genotype–phenotype correlation of IRDs. This has fueled research into therapeutic development over the recent years. Animal models are required for pre-clinical efficacy assessment. Non-human primates (NHP) are ideal due to the anatomical and genetic similarities shared with humans. However, developing NHP disease to recapitulate the disease phenotype for specific IRDs may be challenging from both technical and cost perspectives. This review discusses the currently available NHP IRD models and the methods used for development, with a particular focus on gene-editing technologies.

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“…Several clinical trials are ongoing for the treatment of Leber congenital amaurosis [ 31 , 32 ], retinitis pigmentosa [ 33 ], and corneal dystrophies [ 34 ], among others. Regarding ACHM, some studies aiming to restore CNGA3 and CNGB3 expression by gene replacement are in progress [ 35 , 36 , 37 ]. For instance, one has the objective of evaluating the long-term safety and efficacy of subretinal gene therapy on CNGA3 -related ACHM [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

“…For instance, one has the objective of evaluating the long-term safety and efficacy of subretinal gene therapy on CNGA3 -related ACHM [ 38 ]. Additionally, it is being explored whether the ciliary neurotrophic factor (CNTF) function, which protects cone photoreceptors from degeneration in several non-human models, could be translated to human ACHM patients carrying CNGB3 mutations [ 37 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

High-Efficiency CRISPR/Cas9-Mediated Correction of a Homozygous Mutation in Achromatopsia-Patient-Derived iPSCs

Siles

Gaudó

Pomares

2023

IJMS

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Achromatopsia is an autosomal recessive disorder, in which cone photoreceptors undergo progressive degeneration, causing color blindness and poor visual acuity, among other significant eye affectations. It belongs to a group of inherited retinal dystrophies thatcurrently have no treatment. Although functional improvements have been reported in several ongoing gene therapy studies, more efforts and research should be carried out to enhance their clinical application. In recent years, genome editing has arisen as one of the most promising tools for personalized medicine. In this study, we aimed to correct a homozygous PDE6C pathogenic variant in hiPSCs derived from a patient affected by achromatopsia through CRISPR/Cas9 and TALENs technologies. Here, we demonstrate high efficiency in gene editing by CRISPR/Cas9 but not with TALENs approximation. Despite a few of the edited clones displaying heterozygous on-target defects, the proportion of corrected clones with a potentially restored wild-type PDE6C protein was more than half of the total clones analyzed. In addition, none of them presented off-target aberrations. These results significantly contribute to advances in single-nucleotide gene editing and the development of future strategies for the treatment of achromatopsia.

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Achromatopsia: Genetics and Gene Therapy

Cited by 32 publications

References 94 publications

Analysis of Suspected Achromatopsia by Multimodal Diagnostic Testing

Analysis of Suspected Achromatopsia by Multimodal Diagnostic Testing

Developing Non-Human Primate Models of Inherited Retinal Diseases

High-Efficiency CRISPR/Cas9-Mediated Correction of a Homozygous Mutation in Achromatopsia-Patient-Derived iPSCs

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