Voretigene Neparvovec in Retinal Diseases: A Review of the Current Clinical Evidence

Figures & data

Figure 1 Fundus photograph of the left eye of a 33-year-old female with biallelic RPE65 gene mutation demonstrating diffuse pigmentary changes, vascular attenuation, and temporal disc pallor.

Figure 2 Optical coherence tomography images of the right (A) and left (B) macula of a 6-year-old boy with biallelic RPE65 gene mutation. Notice the diffuse loss of the ellipsoid zone except for a small subfoveal island in both eyes. Also note the marked atrophy of the outer nuclear layer (arrows) which slightly increases in thickness in the parafoveal and foveal regions.

Table 1 Summary of the Major Human Clinical Trials Evaluating RPE65 Gene Therapy

Study	Trial Phase	Methods	Main Results
Maguire et al 2008^Citation37	Phase 1	Patient population 3 patients Unilateral worse eye treated 19 to 26 years old Dose 1.5 x10^10 vg Follow-up 1.25 to 4.75 months	Safety No major immune-related adverse events One patient developed a macular hole Visual function outcomes All patients improved in VA, GVF, PLR, and subjective visual function in dim lighting; all had decreased monocular and binocular nystagmus One patient improved in mobility testing
Hauswirth et al 2008^Citation38	Phase 1	Patients population 3 patients Unilateral worse eye treated 21 to 24 years old Dose 5.96 x10^10 vg Follow-up 3 months	Safety No major immune-related adverse events One patient developed foveal thinning Visual function outcomes 2 patients improved in dark-adapted FST All patients reported subjective visual improvement in dim lighting
Bainbridge et al 2008^Citation39	Phase 1	Patient population 3 patients Unilateral worse eye treated 17 to 23 years old Dose 1 x10^11 vg Follow-up 6 to 12 months	Safety No major immune-related adverse events Visual function outcomes One patient improved in microperimetry One patient improved in dark-adapted perimetry One patient improved in mobility testing One patient reported subjective visual improvement in dim lighting
Maguire et al 2009^Citation40	Phase 1/2 dose-escalation	Patient population 12 patients Unilateral, worse eye treated 8 to 44 years old Doses 1.5 x10^10 vg 4.8 x10^10 vg 1.5 x10^11 vg Follow-up 3 to 24 months	Safety No major immune-related adverse events Visual function outcomes 3 low, 3 medium, and 1 high dose patient improved in VA All patients improved in GVF and subjective visual function in dim lighting All 11 patients tested improved in PLR 5 of 7 patients tested improved in FST 4 of 11 patients tested improved in mobility testing
Jacobson et al 2012^Citation43	Phase 1/2 dose-escalation	Patient population 15 patients Unilateral, worse eye treated except for 1 patient who had fellow eye treated because of keratoconus in worse-seeing eye 11 to 30 years old Doses 5.96 x10^10 vg 7.95 x10^10 vg 8.94 x10^10 vg 11.92 x10^10 vg 17.88 x10^10 vg Follow-up 1 to 36 months	Safety No major immune-related adverse events One patient developed a retinal detachment One patient developed choroidal effusion 3 of 5 patients with fovea-involving injections developed foveal thinning One patient with non-fovea-involving injection developed foveal thinning Visual function outcomes 11 of 12 patients tested improved in dark-adapted static VF All except 1 patient improved in FST Mean PLR showed a clinically significant improvement 3 of 6 patients tested improved in mobility testing
Bainbridge et al 2015^Citation45	Phase 1/2 dose-escalation	Patient population 12 patients Unilateral, worse eye treated 6 to 23 years old Doses 1 x10^11 vg 1 x10^12 vg Follow-up 3 years	Safety No major systemic immune-related adverse events 3 patients in the high dose group developed intraocular inflammation 6 of 10 patients with fovea-involving injections had retinal thinning Visual function outcomes One patient improved in VA in both the treated and untreated eyes while 3 patients showed a decline 6 patients improved in dark-adapted perimetry 5 patients improved in microperimetry 3 patients improved in low light navigation
Weleber et al 2016^Citation46	Phase 1/2 dose-escalation	Patient population 12 patients Unilateral, worse eye treated 6 to 39 years old Doses 1.8 x10^11 vg 6 x10^11 vg Follow-up 2 years	Safety No major immune-related adverse events Visual function outcomes 5 patients improved in VA in treated eye while 1 lost VA in both treated and untreated eyes 11 patients improved while 5 patients had decrease in either total or central 30 degrees static VF testing at 1 or more visits 4 patients improved while 2 patients showed decrease in kinetic VF testing One of 4 patients with baseline minimally recordable ERGs showed a small improvement in photopic and scotopic responses 11 patients reported improvements while 1 patient reported worsening in the NEI-VFQ-25
Bennett et al 2016^Citation49	Phase 1 fellow eye sequential treatment	Patient population 11 patients treated The fellow eye which was previously not elected for treatment was subsequently treated 11 to 46 years old Dose 1.5 x10^11 vg Follow-up 3 years	Safety No major immune-related adverse events one patient developed bacterial endophthalmitis One patient developed retinal thinning Visual function outcomes One patient improved while 1 patient had worsening in VA 4 patients improved in GVF corresponding to injection site while 1 patient had decreased overall GVF but preserved GVF at injection site 8 of 10 patients tested had improved FST All patients improved in pupillary response 8 of 10 patients tested improved in mobility testing 8 of 8 patients tested showed increased cortical activation on fMRI
Russell et al 2017^Citation51	Phase 3	Patient population 29 patients Worse-seeing eye treated first followed by fellow eye 6–18 days later 4 to 44 years old Dose 1.5 x10^11 vg Follow-up 1 year	Safety No major immune-related adverse events 3 patients developed transient ocular inflammation 2 patients developed retinal tears One patient developed a macular hole Visual function outcomes Bilateral mean MLMT change score was greater in treated versus control (1.8 vs 0.2), meeting primary study endpoint Mean FST improvement >2 log units in treated versus no change in controls Mean change in sum total degrees for GVF was +302.1 in treated versus −76.7 in controls Mean macular threshold on HVF improved by 7.7 dB in treated versus 0.2 dB in control patients

Abbreviations: dB, decibels; ERG, electroretinogram; FST, full-field sensitivity threshold testing; fMRI, functional magnetic resonance imaging; GVF, Goldmann visual fields; MLMT, multi-luminance mobility testing; NEI-VFQ-25, National Eye Institute visual function questionnaire 25; PLR, pupillary light reflex; VA, visual acuity, VF, visual field; vg, vector genomes.

Figure 3 Image illustrating the set-up of the injection apparatus. A 1-mL syringe containing the prepared voretigene neparvovec is connected to extension tubing and a 41-gauge subretinal injection cannula.

Figure 4 Intraoperative photograph illustrating a fovea-involving subretinal bleb created by injecting 0.3 mL of voretigene neparvovec.

Figure 5 Intraoperative optical coherence tomography imaging can be used to guide the formation of a subretinal bleb of voretigene neparvovec and confirm its proper localization in the subretinal space.

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