The effect of human gene therapy for RPE65-associated Leber’s congenital amaurosis on visual function: a systematic review and meta-analysis

Wang, Xue; Yu, Chaofeng; Tzekov, Radouil; Chen, Jinyuan; Li, Wensheng

doi:10.1186/s13023-020-1304-1

Cited by 55 publications

(48 citation statements)

References 31 publications

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“…This therapy has an acceptable safety profile. However, the recent meta-analysis summarizing the results of six clinical trials, including 164 eyes, showed that efficacy in improving best-corrected visual acuity appears to be limited to 2 years after treatment [ 42 ]. Moreover, some tendency for thinning of the RPE layer faster in the treated eye than in the non-treated one was observed even in the first year after treatment.…”

Section: Discussionmentioning

confidence: 99%

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Novel gene variants in Polish patients with Leber congenital amaurosis (LCA)

Skorczyk-Werner

Niedziela

Stopa

et al. 2020

Orphanet J Rare Dis

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Background Leber congenital amaurosis (LCA) is a rare retinal disease that is the most frequent cause of congenital blindness in children and the most severe form of inherited retinal dystrophies. To date, 25 genes have been implicated in the pathogenesis of LCA. As gene therapy is becoming available, the identification of potential treatment candidates is crucial. The aim of the study was to report the molecular basis of Leber congenital amaurosis in 22 Polish families. Methods Single Nucleotide Polymorphism-microarray for LCA genes or Next Generation Sequencing diagnostic panel for LCA genes (or both tests) were performed to identify potentially pathogenic variants. Bidirectional Sanger sequencing was carried out for validation and segregation analysis of the variants identified within the families. Results The molecular background was established in 22 families. From a total of 24 identified variants, 23 were predicted to affect protein-coding or splicing, including 10 novel variants. The variants were identified in 7 genes: CEP290, GUCY2D, RPE65, NMNAT1, CRB1, RPGRIP1, and CRX. More than one-third of the patients, with clinical LCA diagnosis confirmed by the results of molecular analysis, appeared to be affected with a severe form of the disease: LCA10 caused by the CEP290 gene variants. Intronic mutation c.2991+1655A>G in the CEP290 gene was the most frequent variant identified in the studied group. Conclusions This study provides the first molecular genetic characteristics of patients with Leber congenital amaurosis from the previously unexplored Polish population. Our study expands the mutational spectrum as we report 10 novel variants identified in LCA genes. The fact that the most frequent causes of the disease in the studied group of Polish patients are mutations in one out of three genes that are currently the targets for gene therapy (CEP290, GUCY2D, and RPE65) strongly emphasizes the importance of the molecular background analyses of LCA in Polish patients.

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Section: Discussionmentioning

confidence: 99%

“…However, there is a hope to prolong the efficacy of the therapy. It is suggested to administer combinatorial agents supplementing the gene therapy to slow retinal degeneration in the long term [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Novel gene variants in Polish patients with Leber congenital amaurosis (LCA)

Skorczyk-Werner

Niedziela

Stopa

et al. 2020

Orphanet J Rare Dis

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“…Currently, AAV vectors are the predominant candidate therapeutic options for tackling ocular diseases with a gene therapy to treat Leber congenital amaurosis based on the delivery of RPE65 by an AAV serotype 2 (AAV-2) vector having already been approved by the Food and Drug Administration (United States) and the European Medicines Agency ( Russell et al, 2017 ). Long-term efficacy of AAV-based RPE65 gene therapies appeared to be limited to 2 years after treatment ( Wang et al, 2020 ), however, a recent follow-up report on therapeutic outcomes confirmed that 86% of patients receiving this approved RPE65 gene therapy (named voretigene neparvovec) maintained improved visual function 4 years after the treatment ( Drack et al, 2019 ). More results are warranted as the study includes a 15-year follow-up of patients (NCT00999609).…”

Section: Genetic Therapies For Treating Irds: From Gene Augmentation mentioning

confidence: 99%

Novel Therapeutic Approaches for the Treatment of Retinal Degenerative Diseases: Focus on CRISPR/Cas-Based Gene Editing

2020

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Inherited retinal diseases encompass a highly heterogenous group of disorders caused by a wide range of genetic variants and with diverse clinical symptoms that converge in the common trait of retinal degeneration. Indeed, mutations in over 270 genes have been associated with some form of retinal degenerative phenotype. Given the immune privileged status of the eye, cell replacement and gene augmentation therapies have been envisioned. While some of these approaches, such as delivery of genes through recombinant adeno-associated viral vectors, have been successfully tested in clinical trials, not all patients will benefit from current advancements due to their underlying genotype or phenotypic traits. Gene editing arises as an alternative therapeutic strategy seeking to correct mutations at the endogenous locus and rescue normal gene expression. Hence, gene editing technologies can in principle be tailored for treating retinal degeneration. Here we provide an overview of the different gene editing strategies that are being developed to overcome the challenges imposed by the post-mitotic nature of retinal cell types. We further discuss their advantages and drawbacks as well as the hurdles for their implementation in treating retinal diseases, which include the broad range of mutations and, in some instances, the size of the affected genes. Although therapeutic gene editing is at an early stage of development, it has the potential of enriching the portfolio of personalized molecular medicines directed at treating genetic diseases.

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“…Despite recent advancements in therapeutic approaches for inherited retinal diseases, there is still a lack of an effective treatment for the main types of IRDs. One of the most advanced therapeutic options is gene therapy, with a treatment currently available for an aggressive form of RP, Leber Congenital Amaurosis, caused by mutations in the RPE65 gene [ 5 , 6 ]. However, to develop treatments for IRDs caused by mutations in all IRDs related-genes, complementary therapeutic options to gene therapy would be much welcomed.…”

Section: Introductionmentioning

confidence: 99%

“…Concerning the retina, a growing list of differentially expressed miRNAs has been described to be involved in retinal diseases, in both humans and animal models [ 21 ]. This includes miR-146a and miR-195 in diabetic retinopathy [ 22 , 23 ]; miR-9, miR-34a, miR-125b, and miR-155 in macular degeneration [ 24 , 25 ]; and miR-125a and miR-17 in retinoblastoma [ 6 , 26 ]. In RP, a common pattern of aberrantly expressed miRNAs, miR-1, miR-133, and miR-142, was observed in four murine models of the disease, involving different genes (rho and rds) and inheritance patterns [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of MicroRNA 6937 Delays Photoreceptor and Vision Loss in a Mouse Model of Retinitis Pigmentosa

et al. 2020

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Inherited retinal dystrophies (IRDs) are a group of rare retinal conditions, including retinitis pigmentosa (RP), caused by monogenic mutations in 1 out of more than 250 genes. Despite recent advancements in gene therapy, there is still a lack of an effective treatment for this group of retinal conditions. MicroRNAs (miRNAs) are a class of highly conserved small non-coding RNAs that inhibit gene expression. Control of miRNAs-mediated protein expression has been described as a widely used mechanism for post-transcriptional regulation in many physiological and pathological processes in different organs, including the retina. Our main purpose was to test the hypothesis that modulation of a group of miRNAs can protect photoreceptor cells from death in the rd10 mouse model of retinitis pigmentosa. For this, we incorporated modulators of three miRNAs in adeno-associated viruses (AAVs), which were administered through sub-retinal injections. The results obtained indicate that inhibition of the miR-6937-5p slows down the visual deterioration of rd10 mice, reflected by an increased electroretinogram (ERG) wave response under scotopic conditions and significant preservation of the outer nuclear layer thickness. This work contributes to broadening our knowledge on the molecular mechanisms underlying retinitis pigmentosa and supports the development of novel therapeutic approaches for RP based on miRNA modulation.

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The effect of human gene therapy for RPE65-associated Leber’s congenital amaurosis on visual function: a systematic review and meta-analysis

Cited by 55 publications

References 31 publications

Novel gene variants in Polish patients with Leber congenital amaurosis (LCA)

Novel gene variants in Polish patients with Leber congenital amaurosis (LCA)

Novel Therapeutic Approaches for the Treatment of Retinal Degenerative Diseases: Focus on CRISPR/Cas-Based Gene Editing

Inhibition of MicroRNA 6937 Delays Photoreceptor and Vision Loss in a Mouse Model of Retinitis Pigmentosa

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