Durability of Voretigene Neparvovec for Biallelic RPE65-Mediated Inherited Retinal Disease

Maguire, Albert M.; Russell, Stephen R.; Chung, Daniel C.; Yu, Zi‐Fan; Tillman, Amy; Drack, Arlene V.; Simonelli, Francesca; Leroy, Bart P.; Reape, Kathleen Z.; High, Katherine A.; Bennett, Jean

doi:10.1016/j.ophtha.2021.03.031

Cited by 93 publications

(44 citation statements)

References 17 publications

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“…While any of these approaches would be immensely beneficial as a treatment option and would offer a single treatment option regardless of the ABCA4 mutation, it is unknown for how long transgenes express, and show improvements in humans, given that retinal degenerations often progress over a lifetime ( Cideciyan et al, 2013 ; Bainbridge et al, 2015 ; Jacobson et al, 2015 ; Gardiner et al, 2020 ; Suh et al, 2021 ). However, the most recent follow-up results from the Voretigene Neparvovec (Luxturna) Phase III clinical trial indicate continued improvements after 4-years ( Maguire et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

The Scope of Pathogenic ABCA4 Mutations Targetable by CRISPR DNA Base Editing Systems—A Systematic Review

2022

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Stargardt macular dystrophy (STGD1) is the most common form of inherited childhood blindness worldwide and for which no current treatments exist. It is an autosomal recessive disease caused by mutations in ABCA4. To date, a variety of gene supplementation approaches have been tested to create a therapy, with some reaching clinical trials. New technologies, such as CRISPR-Cas based editing systems, provide an exciting frontier for addressing genetic disease by allowing targeted DNA or RNA base editing of pathogenic mutations. ABCA4 has ∼1,200 known pathogenic mutations, of which ∼63% are transition mutations amenable to this editing technology. In this report, we screened the known “pathogenic” and “likely pathogenic” mutations in ABCA4 from available data in gnomAD, Leiden Open Variation Database (LOVD), and ClinVar for potential PAM sites of relevant base editors, including Streptococcus pyogenes Cas (SpCas), Staphylococcus aureus Cas (SaCas), and the KKH variant of SaCas (Sa-KKH). Overall, of the mutations screened, 53% (ClinVar), 71% (LOVD), and 71% (gnomAD), were editable, pathogenic transition mutations, of which 35–47% had “ideal” PAM sites. Of these mutations, 16–20% occur within a range of multiple PAM sites, enabling a variety of editing strategies. Further, in relevant patient data looking at three cohorts from Germany, Denmark, and China, we find that 44–76% of patients, depending on the presence of complex alleles, have at least one transition mutation with a nearby SaCas, SpCas, or Sa-KKH PAM site, which would allow for potential DNA base editing as a treatment strategy. Given the complexity of the genetic landscape of Stargardt, these findings provide a clearer understanding of the potential for DNA base editing approaches to be applied as ABCA4 gene therapy strategies.

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Section: Introductionmentioning

confidence: 99%

The Scope of Pathogenic ABCA4 Mutations Targetable by CRISPR DNA Base Editing Systems—A Systematic Review

2022

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“…Despite this, recent clinical trials have made it obvious that gene-based therapies still have a host of challenges that must be overcome if IRDs are to become a curable or at least manageable disease. Questions regarding the long-term safety and durability of AAV-based subretinal vector delivery remain, with long term follow up of patients treated with voretigene neparvovec-showing possible safety signals and a suggestion of visual acuity decline after 4 years (Maguire et al, 2021). While the current IRD clinical trial landscape remains dominated by AAV-based approaches requiring subretinal injection, an increasing number of conveniently administered intravitreal therapeutics such as ASOs are being trialed with encouraging early results.…”

Section: Discussionmentioning

confidence: 99%

“…At 1 year after treatment, the MLMT change score was 1.8 compared to 0.2 in the control group (p 0.0013), with 65% of test subjects and no control subjects able to pass the MLMT at the lowest luminance of 1 lux (Russell et al, 2017). More recently, the three -year outcomes became available and showed a mean MLMT score of 2.4 among the test subjects, with 71% able to pass the MLMT at the lowest luminance, with visual acuity remaining essentially unchanged (Maguire et al, 2021). The most notable complication among the test subjects was a retinal detachment that occurred in a single patient (1 of 21, 4.8%) at around year four, which was probably related to the original surgical intervention and is a known complication of routine vitrectomy.…”

Section: Gene Replacement Strategiesmentioning

confidence: 93%

Gene-Based Therapeutics for Inherited Retinal Diseases

et al. 2022

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Inherited retinal diseases (IRDs) are a heterogenous group of orphan eye diseases that typically result from monogenic mutations and are considered attractive targets for gene-based therapeutics. Following the approval of an IRD gene replacement therapy for Leber’s congenital amaurosis due to RPE65 mutations, there has been an intensive international research effort to identify the optimal gene therapy approaches for a range of IRDs and many are now undergoing clinical trials. In this review we explore therapeutic challenges posed by IRDs and review current and future approaches that may be applicable to different subsets of IRD mutations. Emphasis is placed on five distinct approaches to gene-based therapy that have potential to treat the full spectrum of IRDs: 1) gene replacement using adeno-associated virus (AAV) and nonviral delivery vectors, 2) genome editing via the CRISPR/Cas9 system, 3) RNA editing by endogenous and exogenous ADAR, 4) mRNA targeting with antisense oligonucleotides for gene knockdown and splicing modification, and 5) optogenetic approaches that aim to replace the function of native retinal photoreceptors by engineering other retinal cell types to become capable of phototransduction.

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“…Human gene therapy trials for an inherited retinal disorder reported temporary restoration of some visual function [15][16][17][18], suggesting that of the remaining diseased photoreceptors, a critical number had reached a point of no return [19]. It is unclear if gene therapy impacts constructive remodeling and, if it does, whether this drives some of the restoration of visual function.…”

Section: Introductionmentioning

confidence: 99%

Late-stage rescue of visually guided behavior in the context of a significantly remodeled retinitis pigmentosa mouse model

Kajtna

Tsang

Koch

2022

Cell. Mol. Life Sci.

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Patients with progressive neurodegenerative disorder retinitis pigmentosa (RP) are diagnosed in the midst of ongoing retinal degeneration and remodeling. Here, we used a Pde6b-deficient RP gene therapy mouse model to test whether treatment at late disease stages can halt photoreceptor degeneration and degradative remodeling, while sustaining constructive remodeling and restoring function. We demonstrated that when fewer than 13% of rods remain, our genetic rescue halts photoreceptor degeneration, electroretinography (ERG) functional decline and inner retinal remodeling. In addition, in a water maze test, the performance of mice treated at 16 weeks of age or earlier was indistinguishable from wild type. In contrast, no efficacy was apparent in mice treated at 24 weeks of age, suggesting the photoreceptors had reached a point of no return. Further, remodeling in the retinal pigment epithelium (RPE) and retinal vasculature was not halted at 16 or 24 weeks of age, although there appeared to be some slowing of blood vessel degradation. These data suggest a novel working model in which restoration of clinically significant visual function requires only modest threshold numbers of resilient photoreceptors, halting of destructive remodeling and sustained constructive remodeling. These novel findings define the potential and limitations of RP treatment and suggest possible nonphotoreceptor targets for gene therapy optimization.

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Durability of Voretigene Neparvovec for Biallelic RPE65-Mediated Inherited Retinal Disease

Cited by 93 publications

References 17 publications

The Scope of Pathogenic ABCA4 Mutations Targetable by CRISPR DNA Base Editing Systems—A Systematic Review

The Scope of Pathogenic ABCA4 Mutations Targetable by CRISPR DNA Base Editing Systems—A Systematic Review

Gene-Based Therapeutics for Inherited Retinal Diseases

Late-stage rescue of visually guided behavior in the context of a significantly remodeled retinitis pigmentosa mouse model

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