Gene therapy for <i>RPE65</i>-related retinal disease

Utz, Virginia Miraldi; Coussa, Razek Georges; Antaki, Fares; Traboulsi, Elias I.

doi:10.1080/13816810.2018.1533027

Cited by 91 publications

(51 citation statements)

References 31 publications

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“…Although no effective treatment currently exists for most forms of IRDs, this field has been undergoing dramatic changes over the last decade, mainly due to the development of novel therapeutic modalities that are either gene‐based (gene therapy and targeted pharmacological agents) or non‐gene‐based (regenerative medicine and retinal implants; Kannabiran & Mariappan, ). The recent success of gene therapy for RPE65 deficiency (voretigene neparvovec‐rzyl, i.e., Luxturna) has led to a large number of ongoing gene therapy clinical trials targeting additional IRD‐related genes (Miraldi Utz, Coussa, Antaki, & Traboulsi, ; Ong, Pennesi, Birch, Lam, & Tsang, ). Moreover, due to the marked genetic and etiologic heterogeneity of IRDs, both gene‐based and non‐gene‐based therapies have to be tested on sets of patients with a known genetic diagnosis to prove their efficiency.…”

Section: Discussionmentioning

confidence: 99%

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC)

et al. 2019

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Inherited retinal diseases (IRDs) cause visual loss due to dysfunction or progressive degeneration of photoreceptors. These diseases show marked phenotypic and genetic heterogeneity. The Israeli IRD consortium (IIRDC) was established in 2013 with the goal of performing clinical and genetic mapping of the majority of Israeli IRD patients. To date, we recruited 2,420 families including 3,413 individuals with IRDs. On the basis of our estimation, these patients represent approximately 40% of Israeli IRD patients. To the best of our knowledge, this is, by far, the largest reported IRD cohort, and one of the first studies addressing the genetic analysis of IRD patients on a nationwide scale. The most common inheritance pattern in our cohort is autosomal recessive (60% of families). The most common retinal phenotype is retinitis pigmentosa (43%), followed by Stargardt disease and cone/cone–rod dystrophy. We identified the cause of disease in 56% of the families. Overall, 605 distinct mutations were identified, of which 12% represent prevalent founder mutations. The most frequently mutated genes were ABCA4, USH2A, FAM161A, CNGA3, and EYS. The results of this study have important implications for molecular diagnosis, genetic screening, and counseling, as well as for the development of new therapeutic strategies for retinal diseases.

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Section: Discussionmentioning

confidence: 99%

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC)

et al. 2019

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“…To date, 25 genes have been identified that contribute to the pathogenesis of LCA, both in recessive and dominant modes of inheritance . RPE65 is one of the most well‐known LCA associated genes, being responsible for approximately 5–10% of these cases . Although the resulting phenotype in the majority of the cases appears to be the most severe congenital form, there is an exception in this regard.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, approximately 25 genes have been introduced for LCA . RPE65 is known as a gene for LCA for which 5–10% of LCA cases have a mutation . More than 100 mutations have been reported in the RPE65 gene and in association with LCA, and the majority of these mutations cause diseases with respect to a loss of function and an autosomal recessive inheritance pattern (https://www.ncbi.nlm.nih.gov/clinvar), although hypomorphic alleles with residual activity and milder clinical phenotype have also been reported …”

Section: Introductionmentioning

confidence: 99%

“…Indeed, there has been a pathogen mutation in other gene(s) shown to be associated with other forms of IRD. Second, there have been advances in targeted gene therapy that can reduce vision problems and improve symptoms in LCA patients with early onset or congenital blindness . In this regard, LCA generated by RPE65 is important because this form of LCA is known as a first type of retinal disorder that has shown promising results in clinical trials of gene therapy …”

Section: Introductionmentioning

confidence: 99%

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RPE65 and retinal dystrophy: Report of new and recurrent mutations

Safari

Zare‐Abdollahi

Bushehri

et al. 2020

The Journal of Gene Medicine

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Bachground Leber congenital amaurosis (LCA) is a severe and congenital or early onset form of inherited retinitis pigmentosa (RP). To date, approximately 25 genes have been introduced in relation to LCA. In this regard, retinal pigment epithelium‐specific 65 kDa (RPE65) is a well‐known gene mutation that plays a role in the pathogenesis of 5–10% of LCA cases. Methos Two individuals fromseparate families were subjected to ehole exome sequencing (WES). Causativevariants were searched further assessed using Sanger sequencing. Results Here, two families with mutations in the RPE65 gene show severe and early onset LCA, as expected. In addition to the characterization of the phenotype, by reporting a new mutation (c.1451‐1G>A), we further expand the mutation spectrum of RPE65. Likewise, as an interesting aspect of our study, we report on a previously reported RP‐linked mutation associated with severe early onset LCA (c.T200G:p.L67R). Conclusions Considering this variant in different populations, it is likely that it represents a hotspot and affects the function of the coded protein. The variable expressivity of the phenotype can be assumed by the presence of the modifier allele(s) as a result of a different genetic background or the effect of different environments on phenotype expression.

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“…As a virus, AAV is an excellent vector since it has low cytotoxicity and pathogenicity. In December 2017, the FDA approved the first gene therapy product using AAV for an inherited retinal disease(Russell et al, 2017;Miraldi Utz et al, 2018).…”

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confidence: 99%

Peer Review #1 of "Evaluation of AAV-DJ vector for retinal gene therapy (v0.1)"

2019

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The most common virus vector used in gene therapy research for ophthalmologic diseases is the adeno-associated virus (AAV) vector, which has been used successfully in a number of preclinical and clinical studies. It is important to evaluate novel AAV vectors in animal models for application of clinical gene therapy. The AAV-DJ (type 2/type 8/type 9 chimera) was engineered from shuffling eight different wild-type native viruses. In this study, we investigated the efficiency of gene transfer by AAV-DJ injections into the retina. Methods: One microliter of AAV-2-CAGGS-EGFP or AAV-DJ-CAGGS-EGFP vector at a titer of 1.4 × 10e12 vg/ml was injected intravitreally or subretinally in each eye of C57BL/6 mice. We evaluated the transduction characteristics of AAV-2 and-DJ vectors using fluorescence microscopy and electroretinography. Results: The results confirmed that AAV-DJ could deeply transfer gene to photoreceptor layer with intravitreal injection and has an efficient gene transfer to various cell types especially the Mueller cells in the retina. Retinal function was not affected by AAV-DJ infection or ectopic EGFP expression. Conclusions: The AAV-DJ vector efficiently induces the reporter gene in both the inner and outer murine retina without functional toxicity. These data indicated that the AAV-DJ vector is a useful tool for the gene therapy research targeting retinal disorders.

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Gene therapy for RPE65-related retinal disease

Cited by 91 publications

References 31 publications

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC)

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC)

RPE65 and retinal dystrophy: Report of new and recurrent mutations

Peer Review #1 of "Evaluation of AAV-DJ vector for retinal gene therapy (v0.1)"

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