Luxturna (voretigene neparvovec-rzyl) / Novartis, The Children’s Hospital of Philadelphia, Roche - LARVOL DELTA

Sustained improvement in dark-adapted sensitivity but not BCVA after voretigene neparvovec treatment in a mainland Chinese child with biallelic RPE65-associated LCA2: a case report. (PubMed, Front Pharmacol) - "Although obvious improvement in nyctalopia after early gene therapy has been observed in this patient, all FST data in this study are binocular integrated measurements that cannot be separated to evaluate individual monocular function. Further controlled cohort studies enrolling more Han Chinese participants are still required to verify whether early intervention provides more prominent and definitive relief of nyctalopia for patients carrying biallelic RPE65 variants."

Journal • Gene Therapies • Inherited Retinal Dystrophy • Ophthalmology • Retinal Disorders

Delayed foveal atrophy following early visual improvement after voretigene neparvovec gene therapy in a child. (PubMed, Eye (Lond)) - "These findings underscore the need for long-term follow-up after VN treatment to detect potential late deterioration despite early visual gains. Additionally, patients who exhibit pronounced early FST improvements may benefit from modified or extended immunosuppression to reduce the risk of CRA development."

Journal • Gene Therapies • Inflammation • Inherited Retinal Dystrophy

Voretigene Neparvovec (Luxturna) for Biallelic RPE65-Associated Retinal Dystrophy: Systematic Review. (PubMed, Am J Ophthalmol) - "Voretigene neparvovec-rzyl is associated with improvements in light sensitivity and VF in pediatric patients treated before advanced degeneration, while BCVA gains are variable and usually modest. Chorioretinal atrophy, including perifoveal atrophy in a majority of treated eyes, is a common structural finding warranting monitoring alongside functional benefits."

Journal • Review • Gene Therapies • Inflammation • Inherited Retinal Dystrophy • Ophthalmology • Pediatrics • Retinal Disorders

Reverse amblyopia following gene therapy-induced visual improvement in a child with retinal pigment epithelium-65 inherited retinal dystrophy. (PubMed, BMJ Case Rep) - "Voretigene neparvovec can improve visual function in children with RPE65-associated inherited retinal dystrophy...Despite left-eye treatment, refractive correction and attempted occlusion, the marked visual asymmetry persisted. This case highlights a potential binocular effect of rapid unilateral visual improvement and the need for close monitoring between sequential treatments."

Journal • CNS Disorders • Gene Therapies • Inherited Retinal Dystrophy • Ophthalmology • Strabismus

Interim Results From a Multicenter Observational Safety Study of Patients Treated With Voretigene Neparvovec-rzyl in the United States. (PubMed, Ophthalmology) - "This interim analysis supports the long-term safety of VN in a real-world US cohort, consistent with clinical trial results. CRA did not appear to diminish sustained functional and anatomical benefits with a minimum follow-up of nearly 3 years. Ongoing data collection will further clarify the occurrence, impact, and risk factors for CRA while continuing to monitor VN safety in clinical practice."

Journal • Gene Therapies • Inherited Retinal Dystrophy • Ophthalmology • Retinal Disorders

Trends in the Engineering of Adeno-Associated Virus (AAV) for Precision Gene Delivery to the Central Nervous System (CNS). (PubMed, Int J Mol Sci) - "Despite these challenges, our understanding of AAV structure and technological advances continue to enable researchers to develop innovative strategies that have resulted in groundbreaking, FDA-approved therapeutic products now available for Leber congenital amaurosis (LCA) (Luxturna®), spinal muscular atrophy (SMA) (Zolgensma®), and the two recent gene therapy products for aromatic L-amino acid decarboxylase (AADC) deficiency, Kebilidi® and Upstaza®, which currently hold FDA and EMA approval, respectively. This review aims to highlight recent advances in the field of AAV gene therapy for neurological disorders, identify research gaps, and suggest areas for future investigation to enable potential breakthroughs particularly in neurodegenerative, neurodevelopmental, and neuromuscular disorders. We foresee that more tissue- and cell-specific AAV vectors designed using AI-powered platforms will emerge to precisely and efficiently target specific brain..."

Journal • Review • Alzheimer's Disease • CNS Disorders • Gene Therapies • Genetic Disorders • Inherited Retinal Dystrophy • Movement Disorders • Muscular Atrophy • Parkinson's Disease • Rare Diseases

Post-approval outcomes of voretigene neparvovec (Luxturna®) retinal gene therapy: A systematic review and meta-analysis. (PubMed, Surv Ophthalmol) - "Real-world data therefore confirm clinically meaningful improvements in full-field stimulus threshold consistent with those found in clinical trials, and - unlike Russel and coworkers' pivotal Phase III trial (2017) - suggest a small, but statistically significant, improvement in visual acuity. Chorioretinal atrophy appears commonly in real-world cohorts; however, its clinical significance remains uncertain."

Journal • Retrospective data • Review • Gene Therapies • Ophthalmology • Retinal Disorders

Clinical and genetic characteristics of RPE65-associated inherited retinal degeneration in Koreans. (PubMed, Sci Rep) - "RPE65-associated inherited retinal degeneration (IRD) is a rare autosomal recessive disorder for which a gene therapy (voretigene neparvovec) is available in selected patients with sufficient residual retinal structure...Ultra-widefield fundus autofluorescence was extinguished and ellipsoid zone disruption was diffuse in all eyes. Most Korean patients presented at an advanced stage of disease, suggesting that the therapeutic window for gene therapy may already be limited and underscoring the importance of early recognition and timely genetic diagnosis."

Journal • Gene Therapies • Inherited Retinal Dystrophy • Ophthalmology

Genetic Testing in Inherited Retinal Disease: Current Strategies and Future Directions. (PubMed, J Pers Med) - "Molecular confirmation has become essential for access to novel gene-directed therapies, exemplified by voretigene neparvovec for biallelic RPE65 variants, and is often a prerequisite for clinical trial participation...Emerging tools, including artificial intelligence-assisted variant prioritization, image-to-genotype modeling, and multi-omics analyses, bridge molecular diagnoses with clinical phenotypes, accelerating the transition to targeted therapies. Continued progress will depend on increased access, standardized analytical regulations, and the integration of emerging technologies into routine clinical care."

Journal • Review • Ophthalmology • Retinal Disorders

Precision Medicine in Inherited Retinal Disease: Advances, Challenges, and Future Directions. (PubMed, J Pers Med) - "This advancement has paved the way for targeted therapeutic strategies, exemplified by Luxturna for RPE65-related IRDs. However, several barriers to broader adoption of precision medicine persist, including high costs, varied access to services, and complexities in interpreting genetic variants. While the continued development of innovative therapeutic modalities offers promise for expanding treatment options for IRDs, fully harnessing the potential of current and emerging therapeutic technologies requires addressing existing economic, technological, educational, and infrastructural challenges."

Journal • Review • Gene Therapies • Ophthalmology • Retinal Disorders

Clinical experience with gene therapy for autosomal recessive RPE65-related retinal dystrophy in the Arabian Gulf. (PubMed, Ophthalmol Retina) - "VN treatment improved scotopic vision (FST) in all patients treated before 40 years old and often improved BCVA. Postoperative CRA was universal; ethnicity and sunny climate may have been contributing factors. The possibility of postoperative BCVA loss related to central CRA is an important preoperative counseling point, particularly when preoperative BCVA is functionally useful."

Journal • Gene Therapies • Inherited Retinal Dystrophy • Ophthalmology

Microperimetry is a valuable tool for assessing changes in visual function following voretigene neparvovec-rzyl gene therapy. (PubMed, Ophthalmic Genet) - "These findings were consistent with improvements in daily functioning-particularly in low-light conditions-reported by the patients during medical history assessment during the routine visits. Overall, the findings suggest that microperimetry could be an useful tool for monitoring functional outcomes after gene therapy."

Journal • Gene Therapies

CLTW888A11301: Study of Efficacy and Safety of Voretigene Neparvovec in Japanese Patients With Biallelic RPE65 Mutation-associated Retinal Dystrophy (clinicaltrials.gov) - P3 | N=4 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Inherited Retinal Dystrophy

Four-Year Structural and Functional Outcomes of the First Subretinal Voretigene Neparvovec-rzyl Treatment for RPE65-Associated Inherited Retinal Dystrophy in Korea. (PubMed, Korean J Ophthalmol) - "Perifoveal, fovea-involving chorioretinal atrophy developed between 3 and 6 months and enlarged mainly during the first year, then progressed slowly thereafter. In this Korean patient, VN provided large and durable functional gains over 4 years despite early, severe chorioretinal atrophy, illustrating structural-functional dissociation and underscoring the need for long-term multimodal monitoring in RPE65-associated disease."

Journal • Gene Therapies • Inherited Retinal Dystrophy

Rational for dose selection for intracerebroventricular AAV9 gene therapy using a CTNNB1 gene therapy model (ASGCT 2026) - P1/2 | "These include AAV9- based therapies for spinal muscular atrophy (SMA), administered intravenously (Zolgensma™) or intrathecally (Itvisma™); an intravenously delivered AAV-based therapy for Duchenne muscular dystrophy (Elevidys™); and AAV2-based therapies delivered subretinally to the eye (Luxturna™) or directly to the brain parenchyma (e.g. intraputaminal administration of Upstaza™)...Prioritizing CNS mRNA expression as an efficacy reference point, while achieving exposures at least two-fold below the NOAEL with supportive safety data, enables ethically justified first-in-human dosing decisions in AAV-based CNS gene therapy trials. This framework is intended to inform dose selection strategies across emerging CNS gene therapy programs beyond a single indication."

First-in-human • Gene therapy • CNS Disorders • Developmental Disorders • Duchenne Muscular Dystrophy • Gene Therapies • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Rare Diseases • CTNNB1

Review of Viral Shedding Profiles in Approved AAV-Based Gene Therapy Products: Implications for Safety and Environmental Impact (ASGCT 2026) - "The GTPs were categorized based on their route of administration: locally administered (Luxturna, Upstaza, Glybera, Adstiladrin) and systemically administered (Beqvez, Roctavian, Hemgenix, Elevidys, Zolgensma)...Given that AAV is non-pathogenic to humans, it is feasible to standardize and simplify viral shedding monitoring in clinical studies. The standardization could streamline sampling schedules, reducing the burden on patients while still generating sufficient data to address potential transmission and environmental risks in compliance with regulatory requirements."

Clinical • Gene therapy • Review • Duchenne Muscular Dystrophy • Gene Therapies • Hematological Disorders • Hemophilia • Hemophilia A • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Rare Diseases

Nonclinical Toxicity Study Duration in AAV Gene Therapy Development: Evidence from Industry Survey Supports Adequacy of Short-Term Assessments (ASGCT 2026) - "These findings aligned with regulatory reviews of approved AAV products (e.g., Zolgensma, Luxturna, Roctavian) that consistently demonstrated the adequacy of ≤3-month studies for approved and marketed products. Conclusion The outcome of this survey supports a risk-based, science-driven approach to in vivo study duration, emphasizing that shorter-term studies are generally sufficient for identifying relevant toxicities associated with AAV-based gene therapies. Embracing this approach can reduce animal use, accelerate development timelines, and support harmonized regulatory expectations for AAV gene therapy products."

Gene therapy • Gene Therapies

Creating Novel Retinal Targeting rAAV Capsids With Scalable, Clinically Compatible Manufacturing (ASGCT 2026) - "So far, Luxturna remains the only regulatory approved product available, but there are more than 20 in clinical development...The selected next-generation retinal-targeting rAAV capsids are thus positioned for efficient translation into preclinical and clinical programs using established clinical-grade workflows. A commercial license is required for any clinical or commercial application involving AAVs developed using Revvity technologies."

Clinical • Genetic Disorders

Single-cell and spatial transcriptomic analyses of gene therapy-associated retinal inflammation in non-human primates. (PubMed, Mol Ther Adv) - "We assessed the ocular immune response to subretinal AAV gene therapy in two non-human primates (NHPs): NHP1 received bilateral AAV2-CAG-hRPE65 (voretigene neparvovec) at clinical dose; NHP2 received AAV8-GRK1-hRPGRco alongside an analogous mScarlet reporter vector in separate blebs...Adjunctive intravitreal anti-TNF-α (adalimumab) did not mitigate this chronic anti-viral response. Spatial transcriptomic analysis and immunohistochemistry localized monocytic phagocytes to the subretinal space, consistent with upregulated cytokines (MCP-1/CCL2, IP-10/CXCL10, IL-8/CXCL8, and IL-6), implicating these cells in driving local inflammation. These findings elucidate the mechanism of GTAU and identify potential therapeutic targets to prevent immune-mediated complications in retinal gene therapy."

Journal • Gene Therapies • Inflammation • Ocular Inflammation • Ophthalmology • Retinal Disorders • Uveitis • CCL2 • CXCL10 • CXCL8 • IL6

Voretigene Neparvovec Gene Therapy in Clinical Practice: A 12-Month, Single-Center, In-Depth Analysis of Beneficial and Adverse Drug Effects. (PubMed, Transl Vis Sci Technol) - "Our findings confirmed the visual function improvements following VN and the relatively high prevalence of CRA, which seems to impact negatively only on SKVF enlargement. These findings are useful to better understand risks and benefits of VN gene therapy."

Journal • Diabetic Retinopathy • Gene Therapies • Inherited Retinal Dystrophy • Retinal Disorders

Evaluation of Ocular Adverse Event Disproportionality for LUXTURNA® (voretigene neparvovec-rzyl) (ARVO 2026) - "Conclusions LUXTURNA® provides meaningful and durable visual benefit for patients with RPE65-mediated disease but real-world pharmacovigilance data reveal CRA as an emerging long-term concern. Continued post-marketing surveillance and mechanistic studies are needed to optimize patient selection, injection techniques, and monitoring strategies, and to refine the overall benefit–risk assessment for this first-in-class retinal gene therapy."

Adverse events • Cataract • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders

Long-term safety and effectiveness of voretigene neparvovec: 6-Year interim results of the PERCEIVE real-world study (ARVO 2026) - "Visual function for treated eyes improved at Years 1, 2, 3, 4 and 5 as assessed by FST with a mean (SD) change from baseline of −17.4 (19.14; n=250 eyes), −13.8 (16.54; n=254 eyes), −12.3 (13.71; n=152 eyes), −13.7 (15.69; n=61, eyes), -15.6 (13.42; n=11 eyes) decibels, respectively. Conclusions The Year 6 interim analysis of the PERCEIVE study demonstrates the safety and effectiveness of VN with no change to the established risk-benefit profile for VN."

Clinical • Real-world • Real-world evidence • Cataract • Ophthalmology • Retinal Disorders

Genetic polymorphism is associated with ocular gene therapy toxicity risks in mice (ARVO 2026) - "Purpose Since the approval of Luxturna® by the U.S. Food and Drug Administration (FDA) in 2017, the number of clinical trials for ocular gene therapies skyrocketed, outpacing gene therapies for other classes of disorders...Layman Abstract:Some patients with genetically blinding diseases experience worse side effects associated with receiving an ocular gene therapy, but it is not clear why those particular patients are more affected. This study found that the differences in genetic information among individuals unrelated to the disease gene could explain why they respond differently to a gene therapy."

Gene therapy • Preclinical • Inherited Retinal Dystrophy • Ophthalmology

Comparison of Virtual Reality Multi-luminance Orientation and Mobility Test (VR-MLoMT) with Other Outcome Measures in Subjects Followed Long-term after Receiving Voretigene Neparvovec-rzyl Gene Therapy (ARVO 2026) - P1/2, P3 | "Conclusions The results of the novel VR-MLoMT test correlate with other measures used to evaluate visual function as well as with the performance on the MLMT. The VR-MLoMT is a promising measure for reliably quantifying the impact of disease and treatments on functional vision."

Clinical • Gene therapy • Ophthalmology

Gene-Agnostic Therapeutic Strategies for Inherited Retinal Diseases: Neuroprotection and Immunomodulation. (PubMed, Genes (Basel)) - "While gene-specific replacement therapies have achieved landmark success with voretigene neparvovec (Luxturna) for biallelic RPE65-associated retinal dystrophy, developing individual therapies for each genetic subtype remains impractical...Combination strategies simultaneously addressing multiple pathogenic pathways may offer synergistic benefits. Gene-agnostic approaches targeting neuroprotection and immunomodulation offer a therapeutic paradigm capable of benefiting patients across the spectrum of IRD genotypes, potentially transforming treatment for conditions where mutation-specific therapies remain unavailable."

Journal • Review • Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Gene Therapies • Immunology • Inherited Retinal Dystrophy • Macular Degeneration • Ophthalmology • Retinal Disorders • BDNF