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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

Feb 14, 2020

Xue Wang, Chaofeng Yu, Radouil T. Tzekov, Yihua Zhu, and Wensheng Li | Orphanet Journal of Rare Diseases | Vol 15 (49) | 14 Feb 2020 | doi.org/10.1186/s13023-020-1304-1


Abstract

Background

RPE65-associated LCA (RPE65-LCA) is an inherited retinal degeneration caused by the mutations of RPE65 gene and gene therapy has been developed to be a promising treatment. This study aims to evaluate the association between changes in visual function and application of gene therapy in patients with RPE65-LCA.


Methods

Several databases (PubMed, Cochrane Library, and Web of Science) were searched for results of studies describing efficacy of gene therapy in patients with RPE65-LCA. Six studies, which included one randomized and five prospective non-randomized clinical trials, 164 eyes met our search criteria and were assessed.


Results

The BCVA significantly improved in treated eyes at 1 yr post treatment by − 0.10 logMAR (95% CI, − 0.17 - -0.04; p = 0·002), while there was no significant difference at 2–3 years post treatment (WMD: 0.01; 95% CI, − 0.00 - 0.02; p = 0·15). FST sensitivity to blue flashes also improved by 1.60 log (95% CI, 0.66–2.55; p = 0.0009), but no significant difference to red flashes (WMD: 0.86; 95% CI, − 0·29–2.01; p = 0.14) at 1 yr. There was no significant difference in central retinal thickness at 1 yr, but central retina in treated eyes appeared thinner at 2–3 years post treatment by 19.21 μm (95% CI, − 34.22 - -4.20; p = 0.01).


Conclusions

Human gene therapy is a pioneering treatment option for RPE65-LCA. Although its efficacy appears to be limited to less than 2 yrs after treatment, it carries the potential for further improvement and prolongation of efficacy.


Background

Leber’s Congenital Amaurosis (LCA) is a heterogeneous group of eye diseases with mostly autosomal recessive inheritance, characterized with nystagmus and severely decreased visual acuity in early infancy and complete blindness by the third-to-forth decade of life [1]. RPE65-associated LCA (RPE65-LCA) is associated with mutations of the RPE65 gene encoding the retinoid isomerohydrolase in the retinal pigment epithelium (RPE), which result in rod-cone type retinal dystrophy [2] [3]. As a cutting-edge approach, human gene therapy was developed to compensate genetic deficiency and improve visual function of RPE65-LCA as early as 2008 [4,5,6]. Since then several studies reported that RPE65 gene therapy could improve visual function in RPE65-LCA; however, the overall level of efficacy remains somewhat uncertain and variable. Therefore, we systemically searched and analyzed the published literature in order to gain a better understanding of the effectiveness of human gene therapy on visual function in RPE65-LCA.


The proof of principle of gene therapy for RPE65-associated IRD was demonstrated in murine and canine models of LCA [15,16,17], in which a recombinant adeno-associated viral vector serotype 2 (AAV2) gene replacement therapy produced encouraging improvements in visual function. This led to a clinical trials programme that confirmed the safety, durable efficacy, and favourable benefit-to-risk profile of voretigene neparvovec (AAV2-hRPE65v2, voretigene neparvovec-rzyl, LUXTURNA™; Spark Therapeutics, Inc, Philadelphia, PA, USA, Novartis, Basel, Switzerland), administered as a (one-time) sub-retinal injection, in improving retinal and visual function in RPE65-mediated IRD [18,19,20,21,22,23,24,25,26,27,28,29,30]. Voretigene neparvovec received marketing authorisation for the US in 2017 [31] and the European Union in 2018 [32] for the treatment of adult and paediatric patients with vision loss due to IRD related to confirmed RPE65 biallelic mutations and who have sufficient viable retinal cells [32].


A precise genetic diagnosis is necessary to establish eligibility for treatment of RPE65-associated IRD and to optimise the use of a precision therapeutic intervention such as voretigene neparvovec in a clinically and genetically heterogeneous group of IRDs. Not only is there a lack of shared criteria for the selection of patients suitable for RPE65 gene therapy, but the cost and complexity of the procedure mean that an equitable and transparent process for evaluating the urgency to treat for eligible patients is also necessary. In the absence of specific national guidance in this area, the goal of this project was to develop a clinical pathway algorithm that sets forth a stepwise process for ophthalmologists and geneticists to make decisions about the correct diagnosis and treatment with voretigene neparvovec of patients with RPE65-associated IRD. Herein, we report the outcomes of a consensus process by a group of Italian experts in IRDs to establish recommendations on the clinical and genetic characteristics necessary to confirm patient eligibility for gene therapy with voretigene neparvovec.



 

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