Voretigene neparvovec-rzyl (Luxturna™)

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 by Jennifer I Lim MD on October 29, 2020.

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 immune response to the virus or the modified protein.[2] There are many different AAVs, from the 12 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 and the presence of the blood–retinal-barrier can help avoiding unintentional spreading of 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 phase3 subjects were studied for long term efficacy and safety.[10] The study showed evidence of continued safety and long term (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.


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 'subretinal injection cannula with a polyamide micro tip with an inner diameter of 41gauge'.[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 inyection cannula introduced via pars plana to each eye on separate days within a close interval, but no fewer than 6 days apart; they recommend to use systemic oral corticosteroids after the administration. [5]

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 age) because of possible dilution or loss of the drug after administration due to actively proliferating retinal cells in this age.


There are none 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 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 vitrectomy surgery, is associated with an increased incidence of cataract development and/or progression.


  • The cost of the drug is around 850000 USD per therapy ( 425000 USD per eye) which hinders its access to most patients.[11] The cost however, may be covered by medical insurances in the USA.[11]
  • It is important to note that the treatment does not restore normal vision, and some patient may experience permanent vision loss or reduction of central visual acuity.[11] 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'.[11] It needs the participants to avoid obstacles while navigation.
  • 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.[12]
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. 11.0 11.1 11.2 11.3 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
  12. 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.