Medical Policy

This document addresses the use of gene therapy to treat inherited ophthalmic disease. Therapy can involve the supplementation of a defective gene or the introduction of a factor to decrease disease progression. Currently, only voretigene neparvovec-rzyl (Luxturna^®, Spark Therapeutics, Philadelphia, PA), a gene replacement therapy intended to treat retinal dystrophies caused by biallelic RPE65 gene mutations, has been approved by the FDA.

Note: For a high-level overview of this document, please see “Summary for Members and Families” below.

Medically Necessary:

The use of voretigene neparvovec-rzyl is considered medically necessary in individuals who meet all of the following criteria:

1. A diagnosis of retinal dystrophy due to confirmed RPE65 mutation(s) in both alleles; and
2. At least 1 year of age; and
3. For each eye indicated for treatment, sufficient viable retinal cells as determined by non-invasive means, such as optical coherence tomography (OCT) and/or ophthalmoscopy as evidenced by one of the following:
   1. An area of retina within the posterior pole of greater than 100 µm thickness shown on OCT; or
   2. Three or more disc areas of retina without atrophy or pigmentary degeneration within the posterior pole; or
   3. Remaining visual field within 30 degrees of fixation as measured by a III4e isopter or equivalent;
      and
4. For each eye indicated for treatment, have not had intraocular surgery within 6 months.

Note: Voretigene neparvovec-rzyl has not been adequately studied or in individuals who are pregnant or unwilling to use contraception for 4 months after treatment.

Investigational and Not Medically Necessary:

The use of voretigene neparvovec-rzyl is considered investigational and not medically necessary when the above criteria are not met.

Repeat injections of voretigene neparvovec-rzyl in the same eye are considered investigational and not medically necessary in all cases.

The use of all other gene replacement therapies to treat any ocular condition is considered investigational and not medically necessary.

This document describes clinical studies and expert recommendations, and explains whether use of gene therapy to treat inherited ophthalmic disease is appropriate. The following summary does not replace the medical necessity criteria or other information in this document. The summary may not contain all of the relevant criteria or information. This summary is not medical advice. Please check with your healthcare provider for any advice about your health.

Key Information

This summary describes a gene therapy called voretigene neparvovec-rzyl (brand name Luxturna) used to treat certain inherited eye diseases that cause vision loss. This therapy works by replacing a faulty gene in cells of the eye needed for the retina (the light-sensitive part of the eye) to work properly. This gene therapy is injected into the back of the eye and is only approved for people who have mutations in both copies of the RPE65 gene and still have some healthy retinal cells. It is currently the only gene therapy for eye conditions approved by the U.S. Food and Drug Administration (FDA). Other gene therapies and a newer approach called optogenetics are still being studied and have not been approved. Each therapy has potential benefits and risks, and some may not help or may lead to problems such as eye inflammation, pressure changes, or vision changes. More research is needed to know if these newer treatments are safe and helpful over time.

What the Studies Show

Voretigene neparvovec-rzyl has been shown in studies to help some people with inherited eye problems called retinal dystrophies caused by a genetic mutation. A key study found that people who received the therapy were able to better navigate in low light compared to those who did not get the treatment. Some people also had improvements in light sensitivity, but changes in sharpness of vision were small. The most common side effects were eye inflammation, higher eye pressure, and cataracts, but these were mostly mild or moderate. In rare cases, some people had vision loss possibly related to the injection, though this was not clearly proven. Long-term follow-up showed that some people continued to benefit for several years. However, the benefits varied, and in some cases, vision gains were temporary. Some small studies showed that gene therapy helped improve vision in children with rare forms of blindness, but these results need to be confirmed in larger trials. Repeat treatment in the same eye has not been studied and is not currently recommended. For other gene therapies and optogenetic treatments, early studies have shown promise, but more research is needed to understand who may benefit, how long the effects last, and what risks may occur.

When is Voretigene Neparvovec-rzyl Clinically Appropriate?

Voretigene neparvovec-rzyl may be appropriate in these situations:

• The person has a confirmed diagnosis of retinal dystrophy due to mutations in both copies of the RPE65 gene; and
• Is at least 1 year old; and
• For each eye treated, there are still enough healthy retinal cells based on non-invasive eye tests (such as optical coherence tomography or ophthalmoscopy). This includes at least one of the following:
  • Retinal thickness in the center area is more than 100 micrometers; or
  • At least three areas of retina without scarring or pigment changes; or
  • Visual field that remains within 30 degrees of central vision; and
• Has not had eye surgery in that eye within the past 6 months.

When is this not Clinically Appropriate?

Voretigene neparvovec-rzyl is not considered appropriate if the criteria above are not met. Repeat injections in the same eye are also not appropriate because no studies have shown benefit or safety for doing so. Other gene therapies for any eye condition are not considered appropriate because they have not been proven to improve health. Better studies are needed to know if these treatments are safe or effective.

(Return to Description/Scope)

Summary

Gene therapy for inherited retinal dystrophies aims to restore or preserve vision by replacing a defective gene or modifying disease progression. Voretigene neparvovec-rzyl (Luxturna) is the only FDA-approved ocular gene therapy. Luxturna is an adeno-associated virus (AAV2)-mediated gene replacement therapy for individuals with confirmed biallelic RPE65 mutations and evidence of sufficient viable retinal cells. Clinical evidence demonstrates that treatment benefit is dependent on appropriate genetic confirmation, residual retinal structure, and timing of intervention. A randomized phase 3 trial showed clinically meaningful improvements in functional vision and light sensitivity with an acceptable safety profile, with durability of benefit observed for several years in follow-up studies. In contrast, other ocular gene and optogenetic therapies remain investigational, with evidence limited to early-phase or inconclusive trials and unresolved questions regarding durability, optimal patient selection, and long-term safety.

Discussion

Voretigene neparvovec-rzyl

On December 19, 2017, the U.S. FDA approved voretigene neparvovec-rzyl (Luxturna), the first gene replacement therapy approved in the U.S. to treat an inherited disease. Voretigene neparvovec-rzyl is an adeno-associated virus vector-based gene therapy for the treatment of biallelic RPE65 mutation-associated retinal dystrophy. Voretigene neparvovec-rzyl is supplied in single-dose vials to be used in a single eye and is administered via subretinal injection. Treatment must be done separately in each eye, with at least 6 days between procedures. Use of this therapy is limited to those with evidence of viable retinal cells and to those age 12 months or older. Infants younger than 12 months of age are undergoing active retinal cell proliferation and there is a potential for dilution or loss of voretigene neparvovec-rzyl after administration in this population.

FDA approval of voretigene neparvovec-rzyl was primarily based on the results of an open-label, randomised, controlled phase 3 trial (Russell, 2017). A total of 29 individuals aged 3 years or older with Leber congenital amaurosis type 2 (LCA2) due to confirmed biallelic RPE65 gene mutations participated in the study; all with a visual acuity (VA) of 20/60 or worse and/or a visual field less than 20 degrees in any meridian in both eyes, as well as sufficient viable retinal cells in each eye. The intervention group received a subretinal injection of voretigene neparvovec-rzyl in the poorer-seeing eye, followed by an injection into the second eye 6-18 days after the initial injection. A control group of 9 individuals did not receive therapy for 1 year at which time they could cross over and receive recombinant adeno-associated virus voretigene neparvovec-rzyl therapy (AAV2-hRPE65v2). The primary efficacy endpoint was the change from baseline to 1 year in the score of the multi-luminance mobility testing (MLMT), an assessment of functional vision at specified light levels. Secondary efficacy endpoints also included full-field light sensitivity threshold (FST) testing and best-corrected VA (BCVA), each averaged over both eyes. At 1 year, the mean bilateral MLMT score improvement in the intervention group was 1.8 (standard deviation [SD] 1.1) compared to 0.2 (SD 1.0) in the control group for a difference of 1.6 (95% confidence interval [CI], 0.72-2.41, p=0.0013). Mean FST scores in the intervention group improved by 30 days following intervention and remained stable at 1 year. There was no meaningful change in FST scores in the control group at 1 year. The BCVA scores in the intervention group did show an insignificant numerical improvement over the control group. The authors noted this was not unexpected as BCVA is a measure of foveal, cone-mediated function, and the RPE65 gene mutations result in a rod-mediated disease. The most common treatment-related ocular adverse events (AEs) included elevated intraocular pressure, cataract and eye inflammation and were considered mild or moderate. There were no reported serious product-related AEs or harmful immune responses. One individual in the intervention group did experience loss of VA in the first eye which was significant based upon the VA measurement criteria, however, the individual did not report a change in vision. The authors noted the loss might be due to foveal thinning following subretinal injection, however, the analysis was inconclusive.

In an open-label phase 1/2 trial, the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA was evaluated for 3 years following treatment (Bainbridge, 2015). A total of 12 children and young adults (6 to 23 years old) with early-onset, severe retinal dystrophy, caused by mutations in RPE65, were treated with RPE65 gene supplementation. Individuals received treatment in one eye; 4 individuals received a lower dose while the remaining 8 individuals received a higher dose. In addition to a baseline evaluation, individuals underwent interval evaluations for 3 years, measuring VA, contrast sensitivity, color vision, and spectral sensitivities. While there was a greater proportion of individuals with improved retinal sensitivity among those treated with higher versus lower doses, due to the widely differing level of improvement among the individuals and the small number of participants, a dose-response effect may be present but not definitively concluded. Additionally, treatment benefits did not appear to be lasting. Retinal sensitivity improvement was reported within 1 to 2 months following therapy with progressive improvement continuing for 6 to 12 months. Following 12 months, retinal sensitivity declined in the majority of cases, although 2 individuals showed a continued improvement over pre-intervention levels over 3 years. VA was improved in 1 individual who showed a similar improvement in the contralateral untreated eye. The authors noted rAAV2/2 vector carrying the RPE65 cDNA gene therapy led to a “temporary, variable and incomplete restoration of retinal function in humans.”

Bennett and colleagues (2016) assessed the safety and efficacy of administering the treatments in the contralateral eye in a follow-up to the initial study. A total of 11 of the 12 original participants received an injection in the contralateral, untreated eye and were evaluated on a regular basis for 3 years. An individual with glaucoma in the uninjected eye could not be included in this follow-up study. One individual developed bacterial endophthalmitis following the injection. The remaining adverse effects related to the procedure included dellen formation (n=2) and cataracts (n=1), all of which were successfully treated. For the majority of outcomes, results for the second injected eye were compared with results over the same follow-up period for the initial injected eye. In a pooled analysis, results from full-field light sensitivity threshold testing showed robust improvements in both rod and cone function in the contralateral eyes by day 30 through year 3. A pooled analysis also did not show any significant changes in VA from baseline through year 3 in either eye. There were reported significant improvements in mobility testing and pupillary light reflex testing results which lasted through year 3.

Weleber and associates (2016) treated 12 individuals in a small, non-randomized multi-center clinical trial. A total of 8 adults and 4 children with either LCA or severe early-childhood-onset retinal degeneration (SECORD) with varying degrees of VA were included in the study. Individuals received a subretinal injection containing either 1.8 x 10¹¹ (group 1) or 6 x 10¹¹ (group 2) vector genomes (vg) of rAAV2-CBhRPE65. While 9 of the 12 individuals showed an improvement in at least 1 measure of visual function, the specific area and amount of improvement varied among individuals. Two individuals reported a decrease in BCVA or visual field area that was greater in the treated eye compared to the untreated eye. AEs related to the study agent included ocular hyperemia (n=2) and photopsia (n=1). The authors noted that larger studies with longer follow-up are needed to further assess side effects or safety concerns.

Le Meur and colleagues (2018) evaluated the efficacy and tolerance of injections of AAV serotypes 2 and 4 (AAV2/4) RPE65 in an RPE65 gene deficiency LCA in a phase 1/2 study. A total of 9 individuals aged 9 to 42 years with 2 confirmed RPE65 gene mutations were grouped into 3 cohorts based upon age and injected viral vector dose. Cohort 1 consisted of adults who received the lowest dose of viral vector, cohorts 2 and 3 received higher doses of viral vector. Each participant received 2 to 5 simultaneous unilateral subretinal injections with dosages between 1.22 x 10¹⁰ to 4.8 x 10¹⁰ vg into the eye with the greatest visual impairment. All 9 individuals were followed for 1 year and 6 of the individuals agreed to additional follow-up for 2 to 3.5 years. VA loss progression varied among the cohorts. In cohorts 1 and 3, there were no observed alterations in VA. Cohort 2 showed a trend towards improved VA. VA in the treated eye remained stable during the follow-up period. VA in the untreated eye trended toward reduced VA. However, none of the alterations attained statistical significance. Individuals who presented with nystagmus and intermediate initial VA reported the most marked improvements (cohort 2), while individuals in cohort 3 with correct initial VA without nystagmus showed less of an improvement. The authors postulated that this may be related to the clinical modification in nystagmus. Changes in mobility, evaluated using travel time through a maze under different lighting conditions, were not significantly changed from pre-injection through 1 year follow-up. The injections were well tolerated with only transient symptoms reported. An analysis of the mean retinal thickness at 1-, 2-, or 3-year follow-up revealed no alterations in retinal thickness in the treated or untreated eyes. The authors noted that the possibility of retinal thinning may occur and anticipate assessing this factor in further follow-up.

Le Meur and associates compared their current study to previous studies. The researchers increased the number of subretinal injection sites (2-5) compared to earlier studies in an attempt to increase the contact between the viral vector and the retinal surface, but it remains unclear whether this approach provided additional benefit. In addition, the dose increments in this study were smaller than those in previous trials (1.22 x 10¹⁰ to 4.8 x 10¹⁰ versus 1.5 x 10¹⁰ vg to 6.11 x 10¹¹ vg, respectively). The authors noted that the dose used may not have been sufficient to achieve a meaningful response or to prevent further deterioration. The authors concluded that long term follow-up is needed to evaluate the persistence of the effects and evaluate the treatment effect on retinal degeneration.

Maguire and colleagues (2019) reported on the durability of results of individuals participating in earlier dose dependent phase 1 and phase 3 trials. The results included the 4-year follow-up data from a phase 1 study and the 2-year follow-up data from a phase 3 study. The common endpoints included the MLMT performance change within the illuminance range evaluated, FST testing, and BCVA. At year 4, phase 1 individuals who received the same dosage as those individuals in the phase 3 study showed improvements in tests of functional vision and in visual function which were consistent with those in phase 3 study. The authors note that maximal or near maximal effects appear to be observed by day 30 with the gains maintained in year 4. In addition, the authors noted that the safety profile is consistent with vitrectomy and subretinal injection. The study did not include any individuals younger than 4 years of age.

Treatment with voretigene neparvovec-rzyl is limited to individuals at least 1 year old. The Luxturna package insert (PI) label includes information regarding use in the pediatric population:

Treatment with LUXTURNA is not recommended for patients younger than 12 months of age, because the retinal cells are still undergoing cell proliferation, and LUXTURNA would potentially be diluted or lost during cell proliferation.

Studies have shown safety and variable efficacy with variable duration for up to 4 years following injection therapy (Cideciyan, 2008; Fischer, 2024; Le Meur, 2018; Lorenz, 2024; Jacobson, 2012; Maguire, 2009; Maguire, 2021; Testa, 2013). There appears to be limited or no systemic immune response to the subretinal AAV2 vector delivery (Jacobson, 2012). There remain several unknowns related to gene therapy, including which individuals would benefit from therapy and the most efficacious delivery method. Ongoing durability remains a concern (Bennett, 2016; Le Meur, 2017; Weleber, 2016). Progressive perifoveal chorioretinal atrophy has been reported in individuals undergoing voretigene neparvovec-rzyl therapy, although VA improved or remained stable in the majority of individuals (Gange, 2022). At the current time, the safety and efficacy of repeat injections into the same eye have not been evaluated in clinical studies.

Other gene therapies

Clinical trials evaluating the use of gene therapy for other ocular conditions are ongoing. In a randomized phase 2 trial, Fischer and colleagues (2019) evaluated the safety and efficacy of subretinal injections of a functional version of the choroideremia (CHM) gene in 6 men with molecularly confirmed CHM. Among the 6 participants, gene therapy with an adeno-associated virus vector designed to deliver a functional version of the CHM gene was associated with maintenance or improvement of VA over 2 years, although the difference was not significant from control eyes. A number of unknowns remain, including optimal age of treatment (including stage of disease progression), AEs such as iatrogenic retinal detachment from the procedure (1 out of 6 participants in the study developed iatrogenic retinal detachment from the procedure), and optimal patient selection, including whether certain genetic mutations result in better treatment outcomes. A phase 3 trial (STAR) to assess gene therapy to treat those with CHM (NCT03496012) did not meet its primary endpoint - proportion of participants with at least a 15 letter improvement in BVCA from baseline.

In a phase I/II trial, Cehajic-Kapetanovic and associates (2020) reported on the 6-month results of young men with X-linked retinitis pigmentosa who were treated with gene therapy. The trial population consisted of 3 cohorts (n=6 each) who were treated with varying concentrations of adeno-associated viral vector encoding codon-optimized human RPGR (AAV8.coRPGR). The primary outcome was safety; VA was evaluated as a secondary outcome. The study did not show any dose limiting toxicities and did suggest the potential for reversal of visual field loss. Although the early results are promising, this data represent only initial results; additional studies are needed. The use of gene therapy to treat RPGR mutations represents an additional challenge as the gene coding sequence is unstable. The RPGR sequence instability and the lack of understanding about its function could lead to the production of a nonfunctional or deleterious protein for the human retina (Martinez-Fernandez De La Camara, 2020).

A phase 1/2, open-label, single-ascending-dose trial evaluated the CRISPR-Cas9-based gene-editing therapy, EDIT-101, used to treat retinal degeneration due to the IVS26 variant in the CEP290 gene (Pierce, 2024). EDIT-101 was administered via a subretinal injection with varying doses to 14 participants. Approximately 64% of participants experienced meaningful improvements in visual outcomes, such as BCVA and retinal sensitivity, with 79% showing improvement in at least one efficacy measure and 43% in two or more. No serious treatment-related AEs were recorded, although some expected ocular AEs occurred. Observed improvements in vision-related outcomes were particularly noted among individuals with significant baseline dysfunction. The study's small sample size and absence of a sham control were noted as limitations.

Michaelides (2025) reported the results of an open-label, single-arm trial evaluating rAAV8.hRKp.AIPL1 subretinal gene supplementation in treating congenital severe retinal dystrophy, biallelic disease-causing variants in AIPL1. Eligible participants had relative preservation of outer retinal structure at the central macula. Treatment was administered to one eye in 4 affected children aged 1.0-2.8 years. The contralateral eye remained untreated for safety. Treated eyes showed marked and durable improvements in VA (from only light perception at baseline to ~0.9 logMAR mean), functional vision gains, and enhanced visual cortical responses over ~3.5 years, while untreated eyes declined or became unmeasurable; retinal imaging indicated better structural preservation in treated eyes. The therapy was well-tolerated with no serious safety signals, apart from one case of cystoid macular oedema that partially resolved. This therapy is not FDA approved.

The results of early phase 1/2 trials suggest that gene therapy may benefit several ocular diseases, however additional research is needed to further evaluate safety and efficacy as well as to define the characteristics of those who will benefit from therapy (Dimopoulos, 2018; Lam, 2019; Lam, 2024; MacLaren, 2014; Parker, 2014; von Krusenstiern, 2023; Xue, 2018; Yang, 2025). Phase 3 trials have also been published, but no gene therapies have been FDA approved with the exception of voretigene neparvovec-rzyl (Bioussee, 2021; Newman, 2021; Yu-Wai-Man, 2025). Studies evaluating the use of gene therapy to treat non-inherited ocular disease, such as age-related macular degeneration are also underway.

Optogenetics

Optogenetic therapy is a technique currently being evaluated as a more universal therapy for vision restoration. Optogenetic therapy works by introducing ectopic light-responsive proteins to remaining retinal neurons, with the goal of inducing light sensitivity in these non-functioning neurons and restoring vision. This approach has the advantage of being potentially beneficial to a broader range of individuals, as it can address the disease independent of the specific underlying genetic defect. Numerous optogenetic actuators, combined with various promoters, have been used to investigate their potential in vision restoration.

Studies are ongoing regarding a mutation-agnostic multi-characteristic opsin (MCO) gene therapy to treat inherited retinal diseases (IRDs). The therapy uses a near-infrared laser rather than a virus vector-based delivery system. Therapy to treat retinitis pigmentosa, currently identified as MCO-010 (sonpiretigene isteparvovec) (Nanascope Therapeutics, Dallas, TX) has received fast track and orphan drug designation by the FDA.

The STARLIGHT phase 2 open-label trial (Lam, 2025) evaluated the safety and preliminary efficacy of a single intravitreal injection of MCO-010 in 6 adults with advanced Stargardt disease and residual inner retinal structure. Over 48 weeks, MCO-010 was generally well tolerated, with no treatment-related serious AEs, retinal detachment, or endophthalmitis. Most ocular AEs were mild to moderate and manageable with standard therapy. Mean BCVA improved from baseline by 7.2 ETDRS letters at week 12, 4.2 letters at week 24, and 5.5 letters at week 48, with greater gains observed when testing was performed using a low-vision wearable magnifier. Additional functional benefits were supported by modest improvements in visual field sensitivity and participant-reported outcomes, particularly in reading and contrast domains. Overall, the study is limited by its small, heterogeneous sample; open-label, unmasked design; absence of a sham-controlled comparator; potential learning and contralateral eye effects; ceiling effects in some functional measures; and limited follow-up for assessing long-term durability or disease modification, all of which constrain causal inference and generalizability. These factors underscore the need for larger, randomized, masked, sham-controlled trials with longer follow-up to confirm efficacy and durability.

Hereditary retinal dystrophies or IRDs are progressive disorders which typically result in blindness at a young age. There are approximately 220-260 mutations associated with IRDs including the RPE65 mutation (Martinez-Fernandez De La Camara, 2020; Russell, 2017). Missense mutations in the retinal pigment epithelium-specific protein 65 kDa (RPE65) result in a more severe form of the retinal degenerative disease that is associated with photoreceptor dysfunction and degeneration (Cideciyan, 2013). A lack of functional RPE65 results in rod photoreceptor cells that are unable to respond to light, contributing to decreased ability to see in low light conditions and diminished visual fields. As retinal degeneration progresses and cones are affected, the disorder leads to blindness.

More than 25 genes have been associated with LCA; there is no treatment for the majority of these genotypes (Gange, 2022). IRDs attributed to biallelic RPE65 mutations are associated with the subtypes of LCA type 2 and retinitis pigmentosa (RP) type 20. In the United States (U.S.) there are an estimated 1000 to 3000 individuals with biallelic RPE65 mutation-associated retinal dystrophy. Individuals with LCA caused by RPE65 retain a largely normal outer retinal structure as compared to the amount of visual loss, a unique characteristic which makes potentially restoring vision via gene replacement therapy viable (Wright, 2015). However, gene replacement therapy has been shown to provide a partial improvement in visual dysfunction, as evidenced by improved vision, but does not appear to slow photoreceptor degeneration. Prior to the development of gene therapy, there were no pharmacologic treatments available to treat IRDs.

The 2016 American Academy of Ophthalmology (AAO) recommends genetic testing be ordered at the initial visit for individuals with a suspected inherited retinal degenerative disease. The causative mutation can be identified in up to 60-80% of affected individuals, which can guide treatment decisions. The scope of genetic testing recommended varies; multi-gene testing may be necessary when there are multiple causative genes, while single gene analysis might be more appropriate for certain conditions. For diseases such as LCA, which is caused by multiple different genes, it can be more efficient to order a single test which has been designed to specifically evaluate for all of the known causative genes (Stone, 2012).

In 2019, in an attempt to standardize the detection and reporting of disease-causing variants across the genome, the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) published technical standards for interpreting and reporting constitutional copy-number variants (CNVs). The ACMG created 5 variant classification categories which are scored based on an evidence scoring metric: pathogenic, likely pathogenic, uncertain significance, likely benign and benign. This framework establishes a means to clinically interpret sequence variants in terms of a gene-disease relationship. The authors note:

Understanding the validity of a gene-disease association is the first step in selecting appropriate genes to be tested in a clinical setting. Clinical utility of gene sequencing decreases as the evidence for a disease association decreases. Laboratories are responsible for evaluating how the strength of evidence for gene-disease correlation may limit their ability to classify variants as pathogenic or likely pathogenic.

The eye has several unique features which make it a good model for gene therapy. The blood retinal barrier allows for the introduction of antigens without eliciting an inflammatory immune response, known as ocular immune privilege. Treatment is likely to result in long-term or lifetime benefit, due to the non-dividing nature of photoreceptors or retinal pigment epithelium cells. The small size of structures requires only a small amount of therapeutics to be administered. Visualization can be accomplished using several techniques due to the inherent optical clarity of the eye. Also, as many disease processes have a degree of symmetry, one eye can serve as a control for comparison while treating the contralateral eye (Jolly, 2019).

Agents used to deliver gene therapy can be administered by either subretinal or intravitreal injections. Subretinal injections allow for a more precise delivery of the agent into the retinal pigment epithelium (RPE) and photoreceptor area. However, subretinal injections are more invasive and the placement of the subretinal bleb can lead to macular holes and retinal detachment. Intravitreal injections are considered better for targeting the inner retina but are more likely to generate an immunological response as there is the possibility of a wider systemic spread of the agent (Ziccardi, 2019).

Treatment with voretigene neparvovec-rzyl involves the use of a standard three-port pars plana vitrectomy with removal of the posterior cortical vitreous followed by an injection of the vector genome of adeno-associated virus 2 (AAV2).hRPE65v2 into the subretinal space, creating a localized dome-shaped retinal detachment. The localized retinal detachment typically resolves within 14 to 24 hours following surgery. Minimal persistent subretinal fluid at the macula typically resolves within 2 to 3 days.

Warnings and Precautions

Warnings from the FDA PI Label (2022) include the following:

• Endophthalmitis: Use proper aseptic injection technique and monitor for signs and symptoms of infection.
• Permanent decline in visual acuity: Monitor for visual disturbances.
• Retinal abnormalities: Monitor for macular abnormalities, retinal tears or breaks and chorioretinal atrophy. Do not inject in the immediate vicinity of the fovea.
• Increased intraocular pressure: Monitor and manage intraocular pressure elevations.
• Expansion of intraocular air bubbles: Air travel and/or scuba diving is not recommended until any intraocular air bubbles have been absorbed.
• Cataract: Subretinal injection of Luxturna may result in cataract formation or increase in the rate of cataract progression.

In addition, the PI label includes the following language regarding adverse reactions:

The most common adverse reactions (incidence ≥ 5%) in the clinical trials were conjunctival hyperemia, cataract, increased intraocular pressure, retinal tear, dellen (thinning of the corneal stroma), macular hole, subretinal deposits, eye inflammation, eye irritation, eye pain, and maculopathy (wrinkling on the surface of the macula).

Biallelic Mutation: A mutation in both copies of a particular gene that affects the function of both copies.

Gene replacement therapy:  A medical treatment that introduces or alters genetic material to replace the function of a missing or dysfunctional gene with the goal of lessening or eliminating a disease process that results from genetic dysfunction.

Mutation: A change in the usual DNA sequence of a particular gene; the change can be harmful, beneficial or neutral.

Retina: Light sensitive tissue located at the back of the eye which transmits images along the optic nerve to the brain.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

When services are also Investigational and Not Medically Necessary:

Peer Reviewed Publications:

1. Ashtari M, Zhang H, Cook PA, et al. Plasticity of the human visual system after retinal gene therapy in patients with Leber's congenital amaurosis. Sci Transl Med. 2015; 7(296):296ra110.
2. Bainbridge JW, Mehat MS, Sundaram V, et al. Long-term effect of gene therapy on Leber's congenital amaurosis. N Engl J Med. 2015; 372(20):1887-1897.
3. Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008; 358(21):2231-2239.
4. Bennett J, Ashtari M, Wellman J, et al. AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med. 2012;4(120):120ra15.
5. Bennett J, Wellman J, Marshall KA, et al. Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial. Lancet. 2016; 388(10045):661-672.
6. Biousse V, Newman NJ, Yu-Wai-Man P, et al.; LHON Study Group. Long-term follow-up after unilateral intravitreal gene therapy for Leber hereditary optic neuropathy: The RESTORE study. J Neuroophthalmol. 2021; 41(3):309-315.
7. Cehajic-Kapetanovic J, Xue K, Martinez-Fernandez de la Camara C, et al. Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR. Nat Med. 2020; 26(3):354-359.
8. Cideciyan AV, Aleman TS, Boye SL, et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci U S A. 2008; 105(39):15112-15117.
9. Cideciyan AV, Jacobson SG, Beltran WA, et al. Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci U S A. 2013; 110(6):E517-E525.
10. Dalkara D, Goureau O, Marazova K, Sahel JA. Let there be light: gene and cell therapy for blindness. Hum Gene Ther. 2016; 27(2):134-147.
11. Di Iorio V, Karali M, Brunetti-Pierri R, et al. Clinical and genetic evaluation of a cohort of pediatric patients with severe inherited retinal dystrophies. Genes (Basel). 2017; 8(10).
12. Dias MF, Joo K, Kemp JA, et al. Molecular genetics and emerging therapies for retinitis pigmentosa: basic research and clinical perspectives. Prog Retin Eye Res. 2018; 63:107-131.
13. Dimopoulos IS, Hoang SC, Radziwon A, et al. Two-year results after AAV2-mediated gene therapy for Choroideremia: the Alberta experience. Am J Ophthalmol. 2018; 193:130-142.
14. Fischer MD, Ochakovski GA, Beier B, et al. Efficacy and safety of retinal gene therapy using adeno-associated virus vector for patients with choroideremia: a randomized clinical trial. JAMA Ophthalmol. 2019; 137(11):1247-1254.
15. Fischer MD, Simonelli F, Sahni J, et al.; PERCEIVE Study Group. Real-world safety and effectiveness of voretigene neparvovec: results up to 2 years from the prospective, registry-based PERCEIVE study. Biomolecules. 2024; 14(1):122.
16. 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.
17. Hauswirth WW, Aleman TS, Kaushal S, et al. Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008; 19(10):979-990.
18. Jacobson SG, Cideciyan AV, Ratnakaram R, et al. Gene therapy for Leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol. 2012; 130(1):9-24.
19. Jacobson SG, Cideciyan AV, Roman AJ, et al. Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med. 2015; 372(20):1920-1926.
20. Jolly JK, Bridge H, MacLaren RE. Outcome measures used in ocular gene therapy trials: a scoping review of current practice. Front Pharmacol. 2019; 10:1076.
21. Kulbay M, Tuli N, Akdag A, et al. Optogenetics and targeted gene therapy for retinal diseases: unravelling the fundamentals, applications, and future perspectives. J Clin Med. 2024; 13(14):4224.
22. Kumaran N, Moore AT, Weleber RG, Michaelides M. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions. Br J Ophthalmol. 2017; 101(9):1147-1154.
23. Lam BL, Davis JL, Gregori NZ, et al. Choroideremia gene therapy phase 2 clinical trial: 24-month results. Am J Ophthalmol. 2019; 197:65-73.
24. Lam BL, Pennesi ME, Kay CN, et al.; XIRIUS Study Group. Assessment of visual function with cotoretigene toliparvovec in x-linked retinitis pigmentosa in the randomized XIRIUS phase 2/3 study. Ophthalmology. 2024; 131(9):1083-1093.
25. Lam BL, Zak V, Gonzalez VH, et al. Safety and efficacy of MCO-010 optogenetic therapy in patients with Stargardt disease in USA (STARLIGHT): an open-label multi-center Ph2 trial. EClinicalMedicine. 2025; 87:103430.
26. Le Meur G, Lebranchu P, Billaud F, et al. Safety and long-term efficacy of AAV4 gene therapy in patients with RPE65 Leber congenital amaurosis. Mol Ther. 2018 Jan 3;26(1):256-268.
27. Lorenz B, Künzel SH, Preising MN, et al. Single center experience with voretigene neparvovec gene augmentation therapy in RPE65 mutation-associated inherited retinal degeneration in a clinical setting. Ophthalmology. 2024; 131(2):161-178.
28. MacLaren RE, Groppe M, Barnard AR, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014; 383(9923):1129-1137.
29. Maguire AM, High KA, Auricchio A, et al. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009; 374(9701):1597-1605.
30. Maguire AM, Russell S, Chung DC, et al. Durability of voretigene neparvovec for biallelic RPE65-mediated inherited retinal disease: phase 3 results at 3 and 4 years. Ophthalmology. 2021; 128(10):1460-1468.
31. Maguire AM, Russell S, Wellman JA, et al. Efficacy, safety, and durability of voretigene neparvovec-rzyl in rpe65 mutation-associated inherited retinal dystrophy: results of phase 1 and 3 trials. Ophthalmology. 2019; 126(9):1273-1285.
32. Martinez-Fernandez De La Camara C, Cehajic-Kapetanovic J, MacLaren RE. RPGR gene therapy presents challenges in cloning the coding sequence. Expert Opin Biol Ther. 2020; 20(1):63-71.
33. McClements ME, Staurenghi F, MacLaren RE, Cehajic-Kapetanovic J. Optogenetic gene therapy for the degenerate retina: recent advances. Front Neurosci. 2020; 14:570909
34. Michaelides M, Laich Y, Wong SC, et al. Gene therapy in children with AIPL1-associated severe retinal dystrophy: an open-label, first-in-human interventional study. Lancet. 2025; 405(10479):648-657.
35. Moore NA, Bracha P, Hussain RM, et al. Gene therapy for age-related macular degeneration. Expert Opin Biol Ther. 2017; 17(10):1235-1244.
36. Newman NJ, Yu-Wai-Man P, Carelli V, et al.; LHON Study Group. Efficacy and safety of intravitreal gene therapy for Leber hereditary optic neuropathy treated within 6 months of disease onset. Ophthalmology. 2021; 128(5):649-660.
37. Parker MA, Erker LR, Audo I, et al. Three-year safety results of SAR422459 (EIAV-ABCA4) gene therapy in patients with ABCA4-associated stargardt disease: an open-label dose-escalation phase I/IIa clinical trial, cohorts 1-5. Am J Ophthalmol. 2022; 240:285-301.
38. Pierce EA, Aleman TS, Jayasundera KT, et al. Gene editing for CEP290-associated retinal degeneration. N Engl J Med. 2024; 390(21):1972-1984.
39. Pierce EA, Bennett J. The status of RPE65 gene therapy trials: safety and efficacy. Cold Spring Harb Perspect Med. 2015; 5(9):a017285.
40. Ripamonti C, Henning GB, Robbie SJ, et al. Spectral sensitivity measurements reveal partial success in restoring missing rod function with gene therapy. J Vis. 2015;15(15):20.
41. Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017; 390(10097):849-860.
42. Scholl HP, Moore AT, Koenekoop RK, et al.; RET IRD 01 Study Group. Safety and proof-of-concept study of oral QLT091001 in retinitis pigmentosa due to inherited deficiencies of retinal pigment epithelial 65 protein (RPE65) or lecithin: retinol acyltransferase (LRAT). PLoS One. 2015; 10(12):e0143846.
43. Simonelli F, Maguire AM, Testa F, et al. Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther. 2010; 18(3):643-650.
44. Testa F, Maguire AM, Rossi S, et al. Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital Amaurosis type 2. Ophthalmology. 2013; 120(6):1283-1291.
45. von Krusenstiern L, Liu J, Liao E, et al.; XIRIUS Part 1 Study GroupXOLARIS Study Group. Changes in retinal sensitivity associated with cotoretigene toliparvovec in X-linked retinitis pigmentosa with RPGR gene variations. JAMA Ophthalmol. 2023; 141(3):275-283.
46. Weleber RG, Pennesi ME, Wilson DJ, et al. Results at 2 years after gene therapy for RPE65-deficient Leber congenital amaurosis and severe early-childhood-onset retinal dystrophy. Ophthalmology. 2016; 123(7):1606-1620.
47. Wright AF. Long-term effects of retinal gene therapy in childhood blindness. N Engl J Med. 2015; 372(20):1954-1955.
48. Xue K, Jolly JK, Barnard AR, et al. Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia. Nat Med. 2018; 24(10):1507-1512.
49. Yang P, Birch D, Lauer A, et al. Subretinal gene therapy drug AGTC-501 for XLRP phase 1/2 multicenter study (HORIZON): 24-month safety and efficacy results. Am J Ophthalmol. 2025; 271:268-285.
50. Yu-Wai-Man P, Newman NJ, Biousse V, et al.; LHON Study Group. Five-year outcomes of lenadogene nolparvovec gene therapy in leber hereditary optic neuropathy. JAMA Ophthalmol. 2025; 143(2):99-108.
51. Ziccardi L, Cordeddu V, Gaddini L, et al. Gene therapy in retinal dystrophies. Int J Mol Sci. 2019; 20(22).

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Academy of Ophthalmology (AAO). Clinical Statement. Recommendations on clinical assessment of patients with inherited retinal degenerations- 2022. For additional information visit the AAO website: https://www.aao.org/education/clinical-statement/guidelines-on-clinical-assessment-of-patients-with. Accessed on February 25, 2026.
2. Luxturna [Product Information], Philadelphia, PA. Sparks Therapeutics, Inc. Revised May 2022. Available at: https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM589541.pdf. Accessed on December 30, 2025.
3. Nanoscope Therapeutics Inc. A Phase 2b randomized, double-masked, sham-controlled, study to evaluate the efficacy and safety of intravitreal injection of MCO-010 optogenetic therapy in adults with retinitis pigmentosa [RESTORE]. NLM Identifier: NCT04945772. Last updated on March 22, 2024. Available at: https://clinicaltrials.gov/study/NCT04945772?term=NCT04945772&rank=1. Accessed on December 30, 2025.
4. NightstaRx Ltd. Efficacy and safety of AAV2-REP1 for the treatment of Choroideremia (STAR). NLM Identifier NCT03496012. Last updated December 7, 2023. Available at: https://clinicaltrials.gov/ct2/show/NCT03496012?term=03496012&draw=2&rank=1. Accessed on December 30, 2025.
5. Riggs ER, Andersen EF, Cherry AM, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020; 22(2):245-257.
6. Stone EM, Aldave AJ, Drack AV, et al. Recommendations for genetic testing of inherited eye diseases: report of the American Academy of Ophthalmology task force on genetic testing. Ophthalmology. 2012; 119(11):2408-2410.

1. American Association for Pediatric Ophthalmology and Strabismus (AAPOS). Leber’s Congenital Amaurosis. Last updated November 7, 2024. Available at: https://aapos.org/browse/glossary/entry?GlossaryKey=4f79580a-0ea6-44d2-8479-56ab36064d05. Accessed on December 30, 2025.
2. National Institute of Health: U.S. National Library of Medicine. RPE65 gene. Last updated October 6, 2022. Available at: https://ghr.nlm.nih.gov/gene/RPE65. Accessed on December 30, 2025.
3. National Institute of Health: U.S. National Library of Medicine. What is gene therapy? Updated February 28, 2022. Available at: https://medlineplus.gov/genetics/understanding/therapy/genetherapy/. Accessed on December 30, 2025.

SPK-RPE65
timrepigene emparvovec

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member’s contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically.

No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan.

© CPT Only – American Medical Association