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Abstract
Aims To report main outcomes and complications following voretigene neparvovec (Luxturna) treatment in paediatric patients.
Methods Records of patients under the age of 17 treated by subretinal administration of voretigene neparvovec for confirmed biallelic RPE65-mediated inherited retinal dystrophy were retrospectively reviewed. Best-corrected visual acuity (BCVA) and data from spectral-domain optical coherence tomography, ultra-wide-field fundus imaging and Goldmann visual field (VF) were analysed at 12 months follow-up.
Results 12 eyes of six patients (mean age: 7.8 years) were analysed. No intraoperative complications occurred. BCVA significantly improved at 12-month follow-up (mean LogMAR (logarithm of the minimal angle of resolution) BCVA: 1.0±0.8 at baseline vs 0.6±0.3 at 12 months, p=0.001). Mean central macular thickness and central outer nuclear layer thickness did not change at 12 months follow-up. VF V4e isopter did not show significant changes. Postoperatively complications included: elevated intraocular pressure in two eyes of the same patient, a parafoveal lamellar hole at 3 months post-treatment and atrophy on the injection site observed in all eyes except one, which significantly enlarged during 12 months (p=0.008).
Conclusions Most paediatric patients treated by voretigene neparvovec showed a significant increase in visual function at 12 months follow-up. None of the postoperative complications prevented gains in visual function.
- Retina
- Genetics
- Child health (paediatrics)
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information. NA.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Subretinal administration of voretigene neparvovec early in childhood for RPE65-mediated inherited retinal dystrophy has shown encouraging results in terms of efficacy. However, a perifoveal chorioretinal atrophy has been observed in children who underwent post-market treatment.
WHAT THIS STUDY ADDS
The majority of paediatric patients treated by voretigene neparvovec exhibited a significant increase in visual function. The most common complication was atrophy at the injection site, which significantly enlarged over 12 months. Perifoveal atrophy was observed in one eye. None of the observed postoperative complications prevented gains in visual function.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Indications for treatment with voretigene neparvovec in children is still without consensus. Long-term studies are expected to evaluate the evolution of visual acuity and chorioretinal atrophy in these patients.
Introduction
The RPE65 gene encodes a key isomerohydrolase that catalyses the conversion of all-trans-retinyl esters to 11-cis-retinol in the retinoid cycle. Children with biallelic mutation of the RPE65 gene most frequently present with Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (EOSRD) phenotypes, characterised by nystagmus, night blindness, severely altered global electroretinogram responses and progressive loss of visual acuity and visual field (VF), which renders most affected patients legally blind by age 20.
Voretigene neparvovec (VN, Luxturna), administered by subretinal injection after 25-gauge vitrectomy, uses a non-replicating adeno-associated virus (AAV) as a vector to transfer a functional copy of the RPE65 gene into the retinal pigment epithelium cells. VN has been shown to be well tolerated and safe in humans.1–5 A phase III study reported in 2017 led to the US Food and Drug Administration and European Medicines Agency approval of VN6 for the treatment of biallelic RPE65-mediated inherited retinal dystrophy. The study reported 20 treated patients and nine controls, including 40% of patients aged 3–10 years. Functional vision, as assessed by the ability of a subject to navigate a mobility course accurately in different levels of environmental illumination (multi-luminance mobility testing score) was significantly improved in treated patients. A significant improvement was also shown in the treated group for full-field stimulus testing (FST), Goldmann VF (III4e) and macular sensitivity threshold (Humphrey). Reported adverse effects included elevated intraocular pressure (20%), cataract (15%), retinal tear (10%), ocular inflammation (10%), macular hole (5%), maculopathy (5%) and retinal haemorrhage (5%), among the most frequent. More recently it has been reported that improvements in ambulatory navigation, light sensitivity and VF lasted for at least 3–4 years.7 VN administration early in childhood has shown encouraging results in terms of efficacy.7–10 However, a previously undescribed perifoveal chorioretinal atrophy has been observed in 18 eyes of 10 patients (mean age was 11.6 years old, range: 5–20) who underwent post-market VN treatment by subretinal injection.11 The perifoveal chorioretinal atrophy was first noticeable at an average of 4.7 months following surgery, and progressively enlarged during a mean follow-up of 11 months. Despite this atrophy, improvement in visual acuity, FST and VF was evidenced in the majority of patients.
We report here, the main anatomical and functional outcomes, as well as complications, following VN in paediatric patients with RPE65-mediated inherited retinal dystrophy.
Methods
Records of patients≤16 years old treated by VN for confirmed biallelic RPE65-mediated inherited retinal dystrophy between June 2019 and January 2023 at the ophthalmology department of Necker-Enfants Malades University Hospital were retrospectively retrieved from the BaMaRa database of CRMR OPHTARA (Centre de Référence Maladies Rares en ophtalmologie, accredited by French Health Ministry and Europe ERN.Eye). A non-opposition institutional CRMR OPHTARA consent for research on medical files was obtained from all patients. This study was designed in accordance with the tenets of the Declaration of Helsinki.
General data and data from preoperative visit, surgery and 12-month postoperative visit were recorded. The ophthalmological examination included best-corrected visual acuity (BCVA), intra-ocular pressure, biomicroscopy and fundus observations, as well as results from spectral-domain optical coherence tomography (SD-OCT), ultra-wide-field fundus imaging and Goldmann VF. BCVA was measured by trained vision examiners using a standard protocol involving Early Treatment Diabetic Retinopathy Study (ETDRS) charts and letter counts. SD-OCT scans were performed using Heidelberg SD-OCT (Heidelberg, Germany) and the acquisition protocol comprised macular dense scan protocol, stabilised horizontal and vertical macular line scan. According to the nystagmus characteristics, in specific cases where stabilised scans could not be realised, an adapted protocol comprising multiple non-stabilised lines was performed. Central macular thickness and central outer nuclear layer (ONL) thickness were measured using the instrument software. Areas of retinal atrophy were identified on ultra-wide-field fundus imaging (OptosAdvance, Dunfermline, UK). Localisation of the atrophy regarding the site of injection and bleb area was recorded. The largest diameter of the atrophy zone was measured semi-automatically using the measure tool of the manufacturer software at diagnosis and 12 months later. VF was performed using Goldmann perimetry (Haag-Streit, Swiss). The V4e isopter surface of each VF was quantified using a sum total degrees method.6 12 To calculate the sum total degrees for each isopter, the number of degrees between the central fixation point and the point of isopter intersection for each meridian was measured and summed over the 24 meridians.
The eye with the lower vision was treated first. The contralateral eye was treated at variable intervals depending on the patient general context. A single surgeon (AD) performed subretinal VN therapy according to the recommended protocol reported by Russell et al.6 Briefly, the surgical technique was a 25-gauge vitrectomy (Stellaris Elite, Bausch and Lomb). Sclerotomies were located between 2 and 3.5 mm from the limbus, according to the patient’s age. Vitrectomy was performed after induction of posterior vitreous detachment (preservative-free triamcinolone acetonide was used if necessary). Peripheral breaks were ruled out by scleral depression. A single subretinal injection of VN without pre-bleb was performed along the upper vascular arcades, avoiding vascular structures and areas of atrophy, at least 2 mm away from the foveal centre, using a 25/38-gauge needle (Cannula PolyTip 25 g/38 g, MedOne Surgical, Florida, USA). Although the volume of the injection was the same in all eyes (0,3 mL), since the bleb direction was unpredictable, intraoperative foveal detachment was seen only in some patients. A fluid/air exchange was performed inferiorly to the optic nerve disk and all sclerotomies were sutured. A subtenon injection of dexamethasone was administered at the end of the surgery. Patients received 1 mg/kg per day (up to 40 mg/day) of oral prednisone for 7 days, starting 3 days before surgery. Prednisone was then tapered to 0.5 mg/kg per day (up to 20 mg/day) for 5 days, followed by 0.5 mg/kg every other day for 5 days. Topical treatment with a combination of antibiotic and corticosteroid in decreasing doses was prescribed for 5 weeks.
Wilcoxon test was performed to compare preoperative and postoperative data from each eye on GraphPad Prism (V.8.4.0, GraphPad Software, San Diego, California, USA). Letter scores were converted to logarithm of the minimal angle of resolution (LogMAR) to calculate means. Off-chart visual acuity measurements used adaptations of previously reported scales for assigning LogMAR. Counting fingers was set to LogMAR 1.9, hand movements were set to 2.3 and light perception was set to 2.7.13 For statistical comparisons, differences with a p value≤0.05 were considered significant.
Results
From 207 patients registered with LCA or EOSRD phenotypes, six paediatric patients (12 eyes) were treated with VN for confirmed biallelic RPE65-mediated inherited retinal dystrophy. All patients were male. The mean age at treatment was 7.8 years (range 3–16 years). The interval of treatment between eyes varied from 7 days to 9 months. No intraoperative complication occurred. Due to reflux into the vitreous cavity and inadequate bleb formation, a second injection was administered at a different site in two eyes. The estimated volume of the reflux was considered to ensure a total injection volume of 0.3 mL, with 0.1–0.15 mL injected into the second bleb. Intraoperative foveal detachment was observed in seven eyes (n=7/12). The main results are presented in table 1. BCVA improved significantly at 12 months of follow-up (mean LogMAR BCVA: 1.0±0.8 at baseline vs 0.6±0.3 at 12 months, p=0.001). Visual acuity change at 12 months was not significantly different between patients with or without foveal detachment during surgery (LogMAR BCVA −0.6±0.7 vs −0.12±0.04, p=0.06). Mean central macular thickness (CMT) and mean central ONL thickness did not change at 12 months of follow-up (185±29 µm at baseline and 183±37 µm at 12 months; 45±13 µm at baseline and 43±17 µm at 12 months, respectively). A decrease of both CMT and central ONL thickness was observed in four eyes of two patients. Change in ONL thickness at 12 months was not statistically different between eyes with or without intraoperative foveal detachment (3.7±19 µm vs −9±24 µm, p=0.4).
Main anatomical and functional results in paediatric patients after voretigene neparvovec therapy
Goldmann VF V4e isopter was evaluated on 8 of 12 eyes, and did not show significant changes (mean of sum total degrees: 1507±119 at baseline vs 1450+193 at 12 months).
Postoperative ocular complications included: (1) elevated intraocular pressure in both eyes of one patient, who needed topical treatment during the 12-month follow-up, (2) a parafoveal lamellar hole at 3 months that persisted during follow-up and did not preclude gain of visual acuity (figure 1) and (3) atrophy on injection site in most of the patients. Atrophy at the injection site was detected in all eyes except one (n=11/12 eyes, n=12/14 injection sites). The mean time between surgery and atrophy detection was 4.1 months (range: 1–9 months). The mean diameter of the atrophy area significantly increased from 1.3±1 mm (range: 0.5–3.9 mm) at diagnosis to 1.6±1.2 mm (range: 0.5–4.6 mm) 12 months later (p=0.008). In 4 of 14 injection sites, atrophy did not enlarge over 12 months follow-up. We observed an important enlargement of the atrophy around the injection site on both eyes (0.5 mm and 0.7 mm, respectively) of the youngest patient treated at the age of 3 (figure 2). Chorioretinal atrophy areas outside the injection site but within the area of the bleb was detected in one eye (n=1/12 eyes, size=0.7 mm). Persistent or recurrent inflammatory response after completion of oral and topical steroid was not observed in our series.
(A) Patient 1 presented a parafoveal lamellar hole at 3 months follow-up that was not present at 1 month visit. (B) The hole decreased but remained present 12 months later.
(A,B) Patient 5 treated at the age of 3 presented with atrophy around the injection site (blue dot lines) at 6 months visit, which was larger in the left eye. (C,D) Atrophy area enlarged during 12 months follow-up (0.5 mm and 0.7 mm, respectively).
Discussion
In this series of young patients with RPE65-mediated inherited retinal dystrophy, VN has shown to be well tolerated, with significant results regarding visual function. A mean BCVA improvement of −0.4 LogMAR has been observed at 12 months follow-up. The Phase III study reported by Russell et al failed to show significant improvement on BCVA, despite a mean change of 8.1 letters in the intervention group versus 1.6 letters in controls.6 Lorenz et al have recently reported a gain of≥0.3 LogMAR in two of eight paediatric patients (25%), and no patient with loss≥0.3 LogMAR.14 However, a significant increase in visual function has been reported in paediatric series. Deng et al reported a series of 27 eyes from 14 paediatric patients (age range 4–17 years), with a mean visual acuity improvement of+7.5 up to+12.5 ETDRS letters at 12 months follow-up.12 Gerhardt et al have reported in four young children (aged 3–6 years, eight eyes) a marked increase in vision-guided behaviour and in visual acuity, with a mean change of>0.30 LogMAR units 6 months after gene therapy.15 Sengillo et al reported significant vision change that reached statistical significance only in the paediatric population with a mean follow-up of 10 months.16 At 6 months, a mean change of −0.2 LogMAR (SD±0.07) was observed. In particular, six eyes (50%) showed an improvement of one ETDRS line and the remaining six eyes (50%) improved by two ETDRS lines. Interestingly, intraoperative foveal detachment was not associated with a higher function gain in terms of visual acuity. In our study, the majority of eyes showed improved visual function. However, those with foveal detachment during surgery did not demonstrate a significant increase in visual acuity compared with patients without foveal detachment. While there was a tendency towards better outcomes in eyes with foveal detachment, it is important to note that two of these eyes experienced a notable shift from light perception to 20/200 visual acuity. This substantial improvement could potentially skew the perceived effectiveness in this subset of patients. Additionally, the sole eye that experienced no change in visual acuity had intraoperative foveal detachment. Whether foveal detachment should be induced in the paediatric population remains an unsolved key question.
Testa et al have reported six consecutive paediatric patients that showed a significant increase in visual acuity and ONL thickness of the internal ETDRS‐ring on SD-OCT at day 30/45 and day 180, suggesting that improvement of visual acuity could be related to partial recovery of retinal morphology in the perifoveal ring.17 In our series, CMT and central ONL thickness did not show significant change at 12-month follow-up. Deng et al showed a mild but significant decrease in central subfield thickness within the first 1–2 months after treatment. The thickness of the foveal outer nuclear layer remained stable over 12 months of follow-up. We observed a decrease in CMT and central ONL thickness in four eyes of two patients, both showing an improvement in visual acuity. The correlation between BCVA improvement and structural changes in SD-OCT needs to be confirmed on a larger series.
In the phase III study, the mean sum total degrees Goldmann VF using the III4e target nearly doubled in the treated group and decreased in the control group.6 Similarly, Deng et al showed an expansion of the III4e isopter using deux different quantitative methods in 13 eyes of seven patients. In our series, Goldmann VF could not be performed in all patients but no changes were observed for isopter V4e in tested patients
No intraoperative complications occurred in the present series. A few postoperative complications were observed, but they did not disturb the gain of visual function at 12 months. The most frequent postoperatively complication was atrophy on the injection site. The atrophy enlargement was limited for most patients, except for the youngest one. In this patient, atrophy around the injection site enlarged considerably in both eyes during follow-up. Perifoveal atrophy inside the area of the bleb was observed in one eye, as previously reported by Gange et al.11 Ocular conditions, surgical techniques and vector-related factors may predispose patients to retinal atrophy. In this series, an on-label, one-step injection technique was used, with the assistant surgeon controlling the injection pressure, yet this approach may increase the risk of retinal damage. Retinal injury following subretinal injection could result from mechanical trauma to the retinal pigment epithelium due to prolonged needle time in the subretinal space or from high pressure caused by rapid injection flow.18–20 In children, these risks may be exacerbated by the retina’s increased mechanical resistance to bleb formation, compared with the more damaged retinas in older patients. A balance between increased injection time and higher flow should be achieved to ensure safety. Maintaining a known flow at a controlled rate seems to be a key strategy to mitigate tissue trauma.21 Additionally, localised peeling of the internal limiting membrane has also been suggested to reduce the risk of damage to the retinal pigment epithelium.22 However, the progression of atrophy observed in some patients over time may be due to mechanisms beyond surgical trauma, such as toxicity or immune responses to the AAV vector.23 24 The fact that younger children develop extensive and progressive atrophy suggests that these latter mechanisms are more likely involved.
Overall, the decision for early treatment in the paediatric population should carefully consider the patient’s phenotype and disease progression, their ability to cooperate in assessing at least one quantifiable functional measure such as visual acuity (as evaluating the efficacy of gene therapy in very young children can be challenging) and the potential risk of treatment-related complications, such as progressive retinal atrophy.
In conclusion, the majority of paediatric patients treated with VN exhibited a significant increase in visual function at 12-month follow-up. This improvement was not associated with structural changes in SD-OCT or intraoperative foveal detachment. The most common complication was atrophy at the injection site, which significantly enlarged over 12 months. None of the observed postoperative complications prevented gains in visual function. Long-term studies are expected to evaluate the evolution of retinal thickness and chorioretinal atrophy.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information. NA.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by Ethics Committee of the French Society of Ophthalmology (IRB 00008855). Participants gave informed consent to participate in the study before taking part.
Acknowledgments
We thank Dr Marc Abitbol and Dr Olivia Zambrowski who performed electroretinogram in all patients.
References
Footnotes
MPR and DBG contributed equally.
Collaborators N/A.
Contributors AD: study conception, study design, data analysis/interpretation of data and writing and revising of the manuscript. MR: data acquisition, writing and final approval. EB: data acquisition, writing and final approval. NdV: data acquisition. SV: data acquisition, MPR and DBG: study conception, data acquisition, data analysis/interpretation of data and final approval.DBG: guarantor
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests AD, MPR and DBG: Expertise Consulting for Novartis. MR, EB, NdV and SV: No financial disclosures.
Provenance and peer review Not commissioned; externally peer reviewed.