Plasticity of the human visual system after retinal gene therapy in patients with Leber’s congenital amaurosis

Ashtari, Manzar; Zhang, Hui; Cook, Philip A.; Cyckowski, Laura; Shindler, Kenneth S.; Marshall, Kathleen; Aravand, Puya; Vossough, Arastoo; Gee, James C.; Maguire, Albert M.; Baker, Chris I.; Bennett, Jean

doi:10.1126/scitranslmed.aaa8791

Cited by 56 publications

(47 citation statements)

References 60 publications

(120 reference statements)

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“…18 This improvement has remained durable over at least 3 years, with observation ongoing. 18,19 In addition, a subset of participants in this study was enrolled in a separate functional magnetic resonance imaging study 20 that showed increased activation of the visual cortex and evidence of improved function and structure of the visual pathways after intervention. Other RPE65 gene therapy trials, which were administered to only one eye per individual using different gene constructs, vector formulations, or surgical approaches, have shown improvements in retinal function but variable durability of effect.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65 -mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial

et al. 2017

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Summary Background Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness. Methods In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible. Participants were randomly assigned (2:1) to intervention or control using a permuted block design, stratified by age (<10 years and ≥10 years) and baseline mobility testing passing level (pass at ≥125 lux vs <125 lux). Graders assessing primary outcome were masked to treatment group. Intervention was bilateral, subretinal injection of 1·5×1011 vector genomes of voretigene neparvovec in 0·3 mL total volume. The primary efficacy endpoint was 1-year change in MLMT performance, measuring functional vision at specified light levels. The intention-to-treat (ITT) and modified ITT populations were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00999609, and enrolment is complete. Findings Between Nov 15, 2012, and Nov 21, 2013, 31 individuals were enrolled and randomly assigned to intervention (n=21) or control (n=10). One participant from each group withdrew after consent, before intervention, leaving an mITT population of 20 intervention and nine control participants. At 1 year, mean bilateral MLMT change score was 1·8 (SD 1·1) light levels in the intervention group versus 0·2 (1·0) in the control group (difference of 1·6, 95% CI 0·72–2·41, p=0·0013). 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. No product-related serious adverse events or deleterious immune responses occurred. Two intervention participants, one with a pre-existing complex seizure disorder and another who experienced oral surgery complications, had serious adverse events unrelated to study participation. Most ocular events were mild in severity. Interpretation Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable. Funding Spark Therapeutics.

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Section: Introductionmentioning

confidence: 99%

Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65 -mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial

et al. 2017

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“…1 These lasting cortical activations are likely related to structural improvements observed in these subjects, which, in turn, are further strengthened through visual experience. 30–32 …”

Section: Discussionmentioning

confidence: 99%

“…Injections administered in this area of the retina cause preferential right visual pathway strengthening because the right temporal projections from the retina stay on the right visual cortex and do not cross to the left hemisphere. 32 …”

Section: Discussionmentioning

confidence: 99%

The Role of the Human Visual Cortex in Assessment of the Long-Term Durability of Retinal Gene Therapy in Follow-on RPE65 Clinical Trial Patients

et al. 2017

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Purpose Gene therapy (GT) has offered immense hope to individuals who are visually impaired due to RPE65 mutations. While GT has shown great success in clinical trials enrolling these individuals, evidence for stability and durability of this treatment over time is still unknown. Here we explore the value of functional magnetic resonance imaging (fMRI) as an objective measure to independently assess the longevity of retinal GT. Design Individuals with RPE65 mutations, who underwent GT in their worse-seeing eye in a Phase I clinical trial, received a second subretinal injection in their contralateral eye in a follow-on clinical trial. fMRI was longitudinally performed to assess brain responses of RPE65 patients after stimulation of their most recently treated eye before and 1–3 years after GT. Subjects Seven RPE65 subjects who were part of the follow-on clinical trial were separately consented to participate in a longitudinal neuroimaging fMRI study. Methods All subjects underwent fMRI utilizing a 3-Tesla MRI system and a 32-channel head coil. Subjects’ cortical activations were assessed using a block design paradigm of contrast reversing checkerboard stimuli delivered using an MRI compatible video system. Main Outcome Measures The primary parameters being measured in this study are the qualitative and quantitative fMRI cortical activations produced by our subject population in response to the visual task checkerboard stimulus. Results fMRI results showed minimal or no cortical responses before GT. Significant increase in cortical activation lasting at least three years after GT was observed for all subjects. Repeated measures analysis showed significant associations between cortical activations and clinical measures such as full field light sensitivity threshold (FST) for white, red, and blue colors, visual field (VF), and pupillary light reflex (PLR). Conclusions RPE65-subjects showed intact visual pathways, which became responsive and strengthened after treatment. fMRI results independently revealed the efficacy and durability of a one-time subretinal injection. The fMRI results paralleled those recently reported during the long-term clinical evaluations of the same subjects.1 Results from this study demonstrate that fMRI may play an important role in providing complementary information to patients’ ophthalmic clinical evaluation and has utility as an outcome measure for future retinal intervention studies.

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“…Clinical trials for a form of RP called Leber congenital amaurosis slowed photoreceptor death but did not halt degeneration (23)(24)(25)(26)(27)(28)(29)(30)(31)(32). While there are ongoing efforts to improve this therapy, a limitation of gene-specific treatments is the vast genetic heterogeneity of RP, with more than 60 genes associated with the disorder (33)(34)(35).…”

Section: H620q/h620qmentioning

confidence: 99%

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

Zhang¹,

Du²,

Justus³

et al. 2016

Journal of Clinical Investigation

111

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Retinitis pigmentosa (RP) encompasses a diverse group of Mendelian disorders leading to progressive degeneration of rods and then cones. For reasons that remain unclear, diseased RP photoreceptors begin to deteriorate, eventually leading to cell death and, consequently, loss of vision. Here, we have hypothesized that RP associated with mutations in phosphodiesterase-6 (PDE6) provokes a metabolic aberration in rod cells that promotes the pathological consequences of elevated cGMP and Ca 2+, which are induced by the Pde6 mutation. Inhibition of sirtuin 6 (SIRT6), a histone deacetylase repressor of glycolytic flux, reprogrammed rods into perpetual glycolysis, thereby driving the accumulation of biosynthetic intermediates, improving outer segment (OS) length, enhancing photoreceptor survival, and preserving vision. In mouse retinae lacking Sirt6, effectors of glycolytic flux were dramatically increased, leading to upregulation of key intermediates in glycolysis, TCA cycle, and glutaminolysis. Both transgenic and AAV2/8 gene therapy-mediated ablation of Sirt6 in rods provided electrophysiological and anatomic rescue of both rod and cone photoreceptors in a preclinical model of RP. Due to the extensive network of downstream effectors of Sirt6, this study motivates further research into the role that these pathways play in retinal degeneration. Because reprogramming metabolism by enhancing glycolysis is not gene specific, this strategy may be applicable to a wide range of neurodegenerative disorders.Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration , were challenging to interpret because of negative effects on synaptic transmission (45). We therefore altered our approach to limit ablation of Sirt6 to rod photoreceptors with an inducible gene disruption strategy. Using this model, we tested whether upregulation of glycolytic flux through Sirt6 knockout can preserve both rod and cone photoreceptors in a preclinical, Pde6-associated RP model. The Journal of Clinical Investigation R E S E A R C H A R T I C L E ResultsGeneration of experimental and control groups. The third most common cause of autosomal recessive RP is deficiency in the PDE6 enzyme, which controls the depolarization state of rods by regulating cGMP levels (9, 46-48). An established preclinical model for RP involves a homozygous point mutation (H620Q) in the gene months by increasing glucose uptake and utilization for NADPH production in 4 different mouse models of RP (11,12). In our report, we propose a similar strategy that improves both survival and function of degenerating rods and cones. We hypothesized that Pde6-associated RP provokes a metabolic aberration in the rod cells that forces them to succumb to the consequences of elevated cGMP and Ca 2+ via cyclic nucleotide-gated (CNG) channels and Na + /Ca 2+ -K + exchangers (36-39). The histone deacetylase sirtuin 6 (SIRT6) is a transcriptional repressor of glycolytic enzymes that has been extensively studied in the context of metabolism and cancer biology (40). Normally, S...

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Plasticity of the human visual system after retinal gene therapy in patients with Leber’s congenital amaurosis

Cited by 56 publications

References 60 publications

Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65 -mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial

Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65 -mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial

The Role of the Human Visual Cortex in Assessment of the Long-Term Durability of Retinal Gene Therapy in Follow-on RPE65 Clinical Trial Patients

Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration

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