Development of retinal atrophy after subretinal gene therapy with voretigene neparvovec

Reichel, Felix Friedrich; Seitz, Immanuel P.; Wozar, Fabian; Dimopoulos, Spyridon; Jung, Ronja; Kempf, Melanie; Kohl, Susanne; Kortüm, Friederike; Ott, Saskia; Pohl, Lisa; Stingl, Krunoslav; Bartz‐Schmidt, Karl Ulrich; Štingl, Katarína; Fischer, Manuel

doi:10.1136/bjophthalmol-2021-321023

Cited by 31 publications

(14 citation statements)

References 24 publications

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“…Intriguingly, the appearance of the pa-tientʼs retinal lesions are also reminiscent of the lesions that are found to develop in some patients after treatment with voretigene neparvovec [20,21]. Patches of chorioretinal atrophy that confluence over time are otherwise not completely typical for the natural phenotype in the autosomal recessive RPE65-related retinal dystrophy.…”

Section: Discussionmentioning

confidence: 94%

An Atypical Mild Phenotype of Autosomal Recessive RPE65-Associated Retinitis Pigmentosa

Merle,

Kohl,

Reith

et al. 2024

Klin Monbl Augenheilkd

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Section: Discussionmentioning

confidence: 94%

An Atypical Mild Phenotype of Autosomal Recessive RPE65-Associated Retinitis Pigmentosa

Merle,

Kohl,

Reith

et al. 2024

Klin Monbl Augenheilkd

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“…Also, at present, it is unclear whether increased BAF is indeed a sign of improved isomerase activity or a sign of progressive degeneration. This aspect has become even more important as recently there are also a growing number of reports on new or accentuated chorioretinal atrophy at the site of retinotomy, of the bleb, or outside [27,[31][32][33]. In the survey, the estimated incidence of newly observed atrophies was reported to be 15%.…”

Section: Discussionmentioning

confidence: 99%

Current Management of Patients with RPE65 Mutation Associated Inherited Retinal Degenerations in Europe: Results of a 2-Year Follow-Up Multinational Survey

et al. 2023

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Introduction: To evaluate the current management of RPE65-biallelic mutation-associated inherited retinal degeneration (RPE65-IRD) in Europe since market authorization of Voretigene Neparvovec (VN, LuxturnaTM) in 2018. By July 2022, over 200 patients have been treated outside the USA, of whom about 90% in Europe. We conducted among all centers of the European Vision Institute Clinical Research Network (EVICR.net) and health care providers (HCPs) of the European Reference Network dedicated to Rare Eye Diseases (ERN-Eye) the second multinational survey on management of IRDs in Europe elaborated by EVICR.net with a special focus on RPE65-IRD. Methods: An electronic survey questionnaire with 48 questions specifically addressing RPE65-IRD (2019 survey 35) was developed and sent by June 2021 to 95 EVICR.net centers and 40 ERN-EYE HCPs and affiliated members. Of note, 11 centers are members of both networks. Statistical analysis was performed with Excel and R. Results: The overall response rate was 44% (55/124); 26 centers follow RPE65 biallelic mutation-associated IRD patients. By June 2021, 8/26 centers have treated 57 RPE65-IRD cases (1 – 19/center, median 6), and 43 planned for treatment (range 0 – 10/center, median 6). The overall age range was 3 – 52 years, and on average 22% of the patients did not (yet) qualify for treatment (range 2 – 60%/center, median 15%). Main reasons were too advanced (range 0-100, median 75%) or mild disease (range 0-100, median 0). Eighty-three percent of centers (10/12) that follow RPE65 mutation-associated IRD patients treated with VN participate in the PERCEIVE registry (EUPAS31153, http://www.encepp.eu/encepp/viewResource.htm?id=37005). Quality of life and full field stimulus test (FST) improvements had the highest scores of the survey-reported outcome parameters in VN treatment follow-up. Discussion/Conclusion: This second multinational survey on management of RPE65-IRD by EVICR.net centers and ERN-Eye HCPs in Europe indicates that RPE65-IRD might be diagnosed more reliably in 2021 compared to 2019. By June 2021, 8/26 centers reported detailed results including VN treatment. Main reasons for non-treatment were too advanced or mild disease, followed by absence of two class 4 or 5 mutations on both alleles, or because of a too young age. Patient satisfaction with treatment was estimated to be high by 50% of the centers.

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“…For example, there are gene replacement and gene correction studies for the treatment of RPE65-related LCA and RP. VN is an already established FDA-approved therapy, however, its benefits over the long term are still debated with complications arising following injections despite an improvement in visual acuity ( Gange et al, 2022 ; Reichel et al, 2022 ). While base editing and prime editing techniques are safer, more precise, and show high editing frequencies, they still have the risk of off-target genome editing and require split AAV ( Jang et al, 2021 ) or lentiviral delivery ( Suh et al, 2021 ) due to size constraints.…”

Section: Discussionmentioning

confidence: 99%

Gene regulatory and gene editing tools and their applications for retinal diseases and neuroprotection: From proof-of-concept to clinical trial

Altay

Özdemir²,

Afghah³

et al. 2022

Front. Neurosci.

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Gene editing and gene regulatory fields are continuously developing new and safer tools that move beyond the initial CRISPR/Cas9 technology. As more advanced applications are emerging, it becomes crucial to understand and establish more complex gene regulatory and editing tools for efficient gene therapy applications. Ophthalmology is one of the leading fields in gene therapy applications with more than 90 clinical trials and numerous proof-of-concept studies. The majority of clinical trials are gene replacement therapies that are ideal for monogenic diseases. Despite Luxturna’s clinical success, there are still several limitations to gene replacement therapies including the size of the target gene, the choice of the promoter as well as the pathogenic alleles. Therefore, further attempts to employ novel gene regulatory and gene editing applications are crucial to targeting retinal diseases that have not been possible with the existing approaches. CRISPR-Cas9 technology opened up the door for corrective gene therapies with its gene editing properties. Advancements in CRISPR-Cas9-associated tools including base modifiers and prime editing already improved the efficiency and safety profile of base editing approaches. While base editing is a highly promising effort, gene regulatory approaches that do not interfere with genomic changes are also becoming available as safer alternatives. Antisense oligonucleotides are one of the most commonly used approaches for correcting splicing defects or eliminating mutant mRNA. More complex gene regulatory methodologies like artificial transcription factors are also another developing field that allows targeting haploinsufficiency conditions, functionally equivalent genes, and multiplex gene regulation. In this review, we summarized the novel gene editing and gene regulatory technologies and highlighted recent translational progress, potential applications, and limitations with a focus on retinal diseases.

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Development of retinal atrophy after subretinal gene therapy with voretigene neparvovec

Cited by 31 publications

References 24 publications

An Atypical Mild Phenotype of Autosomal Recessive RPE65-Associated Retinitis Pigmentosa

An Atypical Mild Phenotype of Autosomal Recessive RPE65-Associated Retinitis Pigmentosa

Current Management of Patients with RPE65 Mutation Associated Inherited Retinal Degenerations in Europe: Results of a 2-Year Follow-Up Multinational Survey

Gene regulatory and gene editing tools and their applications for retinal diseases and neuroprotection: From proof-of-concept to clinical trial

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