Voretigene neparvovec-rzyl (Luxturna™)

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 by Jason Hsu, MD on September 8, 2023.

Voretigene neparvovec-rzyl (Luxturna™; Spark Therapeutics, Inc.) is an adeno-associated virus (AAV) vector-based gene therapy presented as a single dose intraocular suspension indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy.[1]

Gene Therapy

Gene therapy can be defined as the genetic modification of DNA to produce a therapeutic effect by replacing a mutated gene, adding a missing gene or modifying an existing one. Genes may be introduced into cells through a vector, usually a virus. [2] Adeno-associated viruses (AAV) are used in gene therapy due to their unique biology, simple structure and poorly immunogenic response compared with other viruses[3], but can still trigger an immune response to the virus or the modified protein.[2] Of the 12 AAV serotypes identified so far, AAV2, AAV4, and AAV5 are specific for retinal tissues.[4] Recombinant AAV2 is the most popular serotype in AAV-based research and clinical trials. [4] The structure and accessibility of the retina, in addition to its immune privileged properties that limit inmune response, make it an ideal target organ for genetic therapies. The presence of the blood-retinal-barrier can also help decrease the risk of unintentionally spreading vectors to neighboring tissues as well as to the general circulation.[4] Gene therapy for RPE65 variant-associated retinal dystrophy uses AAV2 vectors to transfect cells with a functioning copy of RPE65 in the RPE cells[5].

RPE65 Gene

RPE65 (retinal pigment epithelium–specific protein 65-kD) gene encodes an enzyme in the retinal pigment epithelium (RPE) that is responsible for regeneration of 11-cis retinol in the visual cycle[6]. Retinitis pigmentosa (RP), Leber congenital amaurosis (LCA) and Fundus albipunctatus have subtypes related to pathogenic variants in RPE65.[7][8][6] The RPE65 gene is located on the short (p) arm of chromosome 1 at position 31 (1p31.3).[6] Biallelic variations in RPE65 lead to photoreceptor degeneration and can cause severe retinal dystrophies.[9]


Phase 1 and phase 3 subjects were studied for long term efficacy and safety.[10] The study showed evidence of long term safety (4 years) with improved navigational ability (Multi-Luminance Mobility Test (MLMT)) and light sensitivity (full-field light sensitivity threshold (FST) testing). The benefit-to-risk ratio was favorable. Phase 3 results at 3 and 4 years confirmed these findings with maintenance of overall improvement in ambulatory navigation, light sensitivity, and visual field with no serious adverse events or deleterious immune responses.[11]


Voretigene neparvovec-rzyl (Luxturna™) is indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy with viable retinal cells.[8][7][5]

Dosage and administration

Spark Therapeutics, Inc. recommends a single dose for each eye of 1.5 x 1011 vector genomes (vg), administered by subretinal injection in a total volume of 0.3 mL.[5] The supplied concentration (5x1012vg/mL) requires a 1:10 dilution prior to administration. The Diluent is supplied in two single-use 2-mL vials.[5] Recommended location of subretinal injection is along the superior vascular arcade, at least 2 mm distal to the center of the fovea to create a subretinal bleb using a 41-gauge subretinal injection cannula with a polyamide micro tip.[5] The retinal vessel and other pathological areas should be avoided during the injection.

Administration should be performed in the surgical suite under controlled aseptic conditions by a surgeon experienced in performing intraocular surgery. It is administered after a vitrectomy procedure through a subretinal injection cannula introduced via the pars plana to each eye on separate days within a close interval, but no fewer than 6 days apart. Use of systemic oral corticosteroids after the administration is also recommended.[5]

The recommended dose is equivalent of 'prednisone at 1mg/kg/day (maximum of 40 mg/day) for a total of 7 days (starting 3 days before administration of LUXTURNA to each eye), and followed by a tapering dose during the next 10 days.'[5]


The drug is not recommended for infants (below 1 year old) because of possible dilution or loss of the drug after administration due to actively proliferating retinal cells at this age.


There are no contraindications listed in the full prescribing brochure.[5]

Warnings & precautions

The following warnings and precautions are listed from the full prescribing brochure.

  • Endophthalmitis: may occur following any intraocular surgical procedure or injection. Use proper aseptic injection technique when administering Luxturna™. Following the injection, monitor patients carefully to permit early treatment of any infection. Advise patients to report any signs or symptoms of infection or inflammation without delay.
  • Permanent decline in visual acuity: may occur following subretinal injection of Luxturna™. Monitor patients for visual disturbances.
  • Retinal abnormalities: may occur during or following the subretinal injection of Luxturna™, including macular holes, foveal thinning, loss of foveal function, foveal dehiscence, and retinal hemorrhage. Monitor and manage these retinal abnormalities appropriately. Do not administer Luxturna™ in the immediate vicinity of the fovea. Retinal abnormalities may occur during or following vitrectomy including retinal tears, epiretinal membrane, or retinal detachment. Monitor patients during and following the injection to permit early treatment of these retinal abnormalities. Advise patients to report any signs or symptoms of retinal tears and/or detachment without delay.
  • Increased intraocular pressure: may occur after subretinal injection of Luxturna™. Monitor and manage intraocular pressure appropriately.
  • Expansion of intraocular air bubbles: Instruct patients to avoid air travel, travel to high elevations or scuba diving until the air bubble formed following administration of LUXTURNA has completely dissipated from the eye. It may take one week or more following injection for the air bubble to dissipate. A change in altitude while the air bubble is still present can result in irreversible vision loss. Verify the dissipation of the air bubble through ophthalmic examination.
  • Cataract: subretinal injection of Luxturna™, especially with concomitant vitrectomy surgery, is associated with an increased incidence of cataract development and/or progression.


A small case series of 23 eyes from 24 patients found evidence of vitritis in 9 eyes (39.1%),[12] which took a median of 89 days to resolve. Six eyes required sub-Tenon triamcinolone to control the inflammation. Four eyes were also noted to have outer retinal infiltrates at the time of the vitritis, which resolved with corticosteroid therapy. The inflammation did not appear to adversely affect visual outcomes.

Chorioretinal Atrophy

Following approval of voretigene, progressive perifoveal chorioretinal atrophy that extended beyond the retinotomy and subretinal bleb site was reported in some patients.[13][14] The etiology is unclear but several theories have been propopsed, including surgical technique, ocular factors, and vector-related inflammation or toxicity. When it develops, the chorioretinal atrophy appears to exceed the natural course of disease. One study evaluating 71 treated eyes found a correlation with greater improvement in dark-adapted full-field scotopic threshold testing, raising the possibility that the atrophy may be a toxic or metabolic sequela of vector-mediated RPE65 expression.[15] In this study, the youngest and oldest patients did not appear to develop atrophy.


  • The cost of the drug is around 850000 USD per therapy ( 425000 USD per eye) which hinders its access to most patients.[16] The cost however, may be covered by medical insurances in the USA.[16]
  • It is important to note that the treatment does not restore normal vision, and some patients may experience permanent vision loss or reduction of central visual acuity.[16] The efficacy of the drug was evaluated using a multi-luminance mobility testing (MLMT) score and not visual acuity.[5] MLMT evaluates the 'lowest light level at which a patient could accurately and with reasonable speed navigate the 5 ft 10 ft course, which was reconfigured at each attempt'.[16] It requires the participants to avoid obstacles while navigating.
  • A cost-effectiveness analysis has shown that voretigene neparvovec is cost-effective compared with standard care when using a lifetime horizon and excluding indirect costs, and using a threshold of $150 000 per quality-adjusted life-year.[17]
Adverse Reactions Subjects n=41 Treated Eyes n=81
Any ocular adverse reaction 27 (66%) 46 (57%)
Conjunctival hyperemia 9 (22%) 9 (11%)
Cataract 8 (20%) 15 (19%)
Increased intraocular pressure 6 (15%) 8 (10%)
Retinal tear 4 (10%) 4 (5%)
Dellen 3 (7%) 3 (4%)
Macular hole 3 (7%) 3 (4%)
Subretinal deposits* 3 (7%) 3 (4%)
Eye inflammation 2 (5%) 4 (5%)
Eye irritation 2 (5%) 2 (2%)
Eye pain 2 (5%) 2 (2%)
Maculopathy 2 (5%) 3 (4%)
Foveal thinning and loss of foveal function 1 (2%) 2 (2%)
Endophthalmitis 1 (2%) 1 (1%)
Foveal dehiscence 1 (2%) 1 (1%)
Retinal hemorrhage 1 (2%) 1 (1%)

Most common adverse reactions (incidence ≥ 5%):

  • Conjunctival hyperemia
  • Cataract
  • Increased intraocular pressure
  • Retinal tear
  • Dellen (thinning of the corneal stroma)
  • Macular hole
  • Subretinal deposits
  • Eye inflammation
  • Eye irritation
  • Eye pain
  • Maculopathy

Regulatory Status

AAV2 gene therapy vector voretigene neparvovec-rzyl (Luxturna™; SparkTherapeutics) was approved by the FDA for use in patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy on December 19, 2017. Spark Therapeutics received breakthrough therapy designation, rare pediatric disease designation, and orphan drug designation.[5]

Additional Resources


  1. Grzegorz Bereta, Philip D. Kiser, Marcin Golczak, et al. Impact of Retinal Disease-Associated RPE65 Mutations on Retinoid Isomerization. Biochemistry 47, 37, 9856-9865. August 23, 2008. doi: 10.1021/bi800905v.
  2. 2.0 2.1 Eugene H. Kaji, MD;Jeffrey M. Leiden, MD, PhD.  Gene and Stem Cell Therapies. JAMA. 2001;285(5):545-550. doi:10.1001/jama.285.5.545    
  3. Maguire AM, Simonelli F, Pierce EA, Pugh EN, Mingozzi F, Bennicelli J, et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. The New England Journal of Medicine. May 2008,  358 (21): 2240–8. 
  4. 4.0 4.1 4.2 Enrico M. Surace, Alberto Auricchio. Versatility of AAV vectors for retinal gene transfer. Vision Research, volume 48, issue 3, February 2008, 353-359.    
  5. 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 Luxturna® (voretigene neparvovec-rzyl) [prescribing information]. Philadelphia, PA 19104: Spark Therapeutics, Inc; 2017.    
  6. 6.0 6.1 6.2 Genetics Home Reference,World Wide Web URL: http://ghr.nlm.nih.gov/    
  7. 7.0 7.1 Maguire AM, High KA, Auricchio A, Wright JF, et al. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009 Nov 7;374(9701):1597-605. doi: 10.1016/S0140-6736(09)61836-5. Epub 2009 Oct 23.    
  8. 8.0 8.1 Dias MF, Joo K, Kemp JA, Fialho SL, et al .Molecular genetics and emerging therapies for retinitis pigmentosa: Basic research and clinical perspectives. Prog Retin Eye Res. 2018 Mar;63:107-131. doi: 10.1016/j.preteyeres.2017.10.004.    
  9. Grzegorz Bereta, Philip D. Kiser, Marcin Golczak, et al. Impact of Retinal Disease-Associated RPE65 Mutations on Retinoid Isomerization. Biochemistry  47, 37, 9856-9865. August 23, 2008. doi: 10.1021/bi800905v. 
  10. Maguire AM, Russell S, Wellman JA, Chung DC, Yu ZF, Tillman A, Wittes J, Pappas J, Elci O, Marshall KA, McCague S, Reichert H, Davis M, Simonelli F, Leroy BP, Wright JF, High KA, Bennett J. Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation-Associated Inherited Retinal Dystrophy: Results of Phase 1 and 3 Trials. Ophthalmology. 2019 Sep;126(9):1273-1285.
  11. Maguire AM, Russell S, Chung DC, Yu ZF, Tillman A, Drack AV, Simonelli F, Leroy BP, Reape KZ, High KA, Bennett J. Durability of Voretigene Neparvovec for Biallelic RPE65-Mediated Inherited Retinal Disease: Phase 3 Results at 3 and 4 Years. Ophthalmology. 2021 Oct;128(10):1460-1468. doi: 10.1016/j.ophtha.2021.03.031. Epub 2021 Mar 30. PMID: 33798654.
  12. Kessel L, Christensen UC, Klemp K. Inflammation after voretigene neparvovec administration in patients with RPE65-related retinal dystrophy. Ophthalmology. 2022 Jun 24:S0161-6420(22)00477-8. doi: 10.1016/j.ophtha.2022.06.018. Epub ahead of print. PMID: 35760216.
  13. Gange WS, Sisk RA, Besirli CG, et al. Perifoveal Chorioretinal Atrophy after Subretinal Voretigene Neparvovec-rzyl for RPE65-Mediated Leber Congenital Amaurosis. Ophthalmol Retina. 2022;6(1):58-64. doi:https://doi.org/10.1016/j.oret.2021.03.016
  14. Reichel FF, Seitz I, Wozar F, et al. Development of retinal atrophy after subretinal gene therapy with voretigene neparvovec. British Journal of Ophthalmology. Published online May 23, 2022:bjophthalmol-2021-321023. doi:10.1136/bjophthalmol-2021-321023
  15. Stingl K, Stingl K, Schwartz H, Reid MW, Kempf M, Dimopoulos S, Kortuem F, Borchert MS, Lee TC, Nagiel A. Full-field scotopic threshold improvement following voretigene neparvovec-rzyl treatment correlates with chorioretinal atrophy. Ophthalmology. 2023 Feb 21:S0161-6420(23)00126-4. doi: 10.1016/j.ophtha.2023.02.015. Epub ahead of print. PMID: 36822437.
  16. 16.0 16.1 16.2 16.3 Darrow JJ. Luxturna: FDA documents reveal the value of a costly gene therapy. Drug Discov Today. 2019;24(4):949‐954. doi:10.1016/j.drudis.2019.01.019
  17. Johnson S, Buessing M, O'Connell T, Pitluck S, Ciulla TA. Cost-effectiveness of Voretigene Neparvovec-rzyl vs Standard Care for RPE65-Mediated Inherited Retinal Disease. JAMA Ophthalmol. 2019 Jul 18;137(10):1115–23.
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