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

Gene therapy outcomes in young patients with RPE65-retinal degeneration. (PubMed, Can J Ophthalmol) - "VN treatment is safe and effective in improving retinal sensitivity in patients under 21 years old with RPE65-LCA despite the occurrence of CRA post-treatment."

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

Biologics-device combinations: Enabling prolonged therapies in the posterior segment ocular disease. (PubMed, Adv Drug Deliv Rev) - "This comprehensive review examines the latest advancements of these combination platforms, including refillable implants (e.g., SUSVIMO®), encapsulated cell technology (e.g., ENCELTO™), and recombinant adeno-associated virus (rAAV) vectors (e.g., LUXTURNA®)...However, substantial hurdles, such as instability caused by material-biologics interactions, potential risks during the sterilization and manufacturing processes, safety risks, and the evolving regulatory landscape, still need to be addressed. Achieving a balance between the stability of biologics and advanced device design, enhancing long-term safety, and developing responsive smart systems with real-time monitoring and feedback capabilities remain crucial for the advancement of next-generation ophthalmic therapies."

Journal • Review • Age-related Macular Degeneration • Diabetic Retinopathy • Macular Degeneration • Ophthalmology • Retinal Disorders

Vision Outcomes in Children Treated With Voretigene Neparvovec for RPE65-Associated Retinopathy. (PubMed, JAMA Ophthalmol) - "This case series study reports VN-treated patients as young as 15 months, confirming visual improvements, although not necessarily VA when off-chart VA conversions were excluded, consistent with previously reported outcomes. Pattern VEPs provided an objective measure of retinogeniculostriate recovery, supporting their use as an outcome measure in future trials for young children with inherited retinal diseases."

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

Mechanisms and Functions of Chromophore Regeneration in the Classical Visual Cycle: Implications for Retinal Disease Pathogenesis and Therapy. (PubMed, Biomolecules) - "Recent therapeutic advances, ranging from gene replacement therapy with RPE65 (voretigene neparvovec, Luxturna®) to small-molecule modulators and antioxidant strategies, underscore the translational potential of targeting chromophore metabolism...We highlight ongoing challenges and critical knowledge gaps to guide future investigations on basic science, translational research, and clinical practice. This review provides a comprehensive overview of the molecular mechanisms, current therapeutic approaches, and outstanding challenges, with a focus on future intervention directions."

Journal • Review • Age-related Macular Degeneration • Genetic Disorders • Inherited Retinal Dystrophy • Macular Degeneration • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa

Gene Therapy for Inherited Retinal Disease: Current Strategies, Personalized Medicine, and Future Implications-A Comprehensive Review. (PubMed, J Pers Med) - "The approval of voretigene neparvovec-rzyl for RPE65-mediated retinal dystrophy marked a pivotal milestone, establishing proof of concept for durable and safe gene replacement therapy. Looking ahead, continued refinements in vector design, CRISPR-based editing strategies, and delivery platforms are expected to expand the therapeutic reach of gene therapy beyond monogenic disorders. With multiple early-phase clinical trials underway for inherited and acquired retinal diseases, the coming decade is poised to bring broader applicability, improved durability, and more accessible gene-based treatments across the spectrum of retinal pathology."

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

Chorioretinal atrophy after Voretigene Neparvovec-therapy in RPE65-mutation-associated IRD: Longitudinal characterization in multimodal imaging. (PubMed, Ophthalmologica) - "This study highlights the crucial role of multimodal imaging in monitoring VN-associated CRA. Differences in lesion detection and size assessment across imaging modalities were observed, with the largest CRA extent detected in BAF imaging. Median visual function remained stable. These findings emphasize the complexity of VN therapy outcomes and the need for close surveillance using combined multimodal imaging to better understand the long-term clinical implications."

Journal

Nonclinical toxicity study duration in AAV gene therapy development: Evidence from industry survey supports adequacy of short-term assessments. (PubMed, Mol Ther Methods Clin Dev) - "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. 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."

Journal • Gene Therapies

Promises past and future - Gene therapy and the actualisation of future expectations. (PubMed, Soc Sci Med) - "The advent of gene therapies such as Zolgensma, Libmeldy, and Luxturna has given rise to new treatment options for several rare conditions, drastically changing the expectations of affected patients...Similarly marginalised issues include for instance assumptions of effectiveness that do not acknowledge the long-term uncertainty of treatment outcomes; and assumptions of profitability that run counter to real-life examples of business failure. As a revolutionary future becomes reality for some patients, such questions are becoming harder to ignore - but are crucially often omitted from discussion about projected change."

Journal • Gene Therapies

Gene Therapy in Rare Genetic Disorders: Current Progress and Future Perspectives. (PubMed, Curr Genomics) - "Gene therapy has achieved significant milestones, with the successful development of therapies like Zolgensma for spinal muscular atrophy and Luxturna for retinal dystrophy...Gene therapy holds transformative potential for the treatment of rare genetic disorders. While recent successes mark a new era in genetic medicine, ongoing research is required to refine delivery mechanisms, overcome immune-related barriers, and ensure ethical and safe therapeutic interventions."

Journal • Review • CNS Disorders • Gene Therapies • Genetic Disorders • Inherited Retinal Dystrophy • Movement Disorders • Muscular Atrophy • Rare Diseases

Factors impacting experience of genetic testing among adults with inherited retinal diseases. (PubMed, J Genet Couns) - "However, additional genetic counseling support is needed for individuals undergoing genetic testing soon after receiving a clinical diagnosis, those with complex family/cultural dynamics, and those receiving inconclusive results. Setting appropriate expectations around outcomes and addressing logistical factors are important for guiding the overall genetic testing experience."

Journal • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa

Clinical and pharmacovigilance safety evaluation of LUXTURNA® (voretigene neparvovec-rzyl). (PubMed, Cutan Ocul Toxicol) - "LUXTURNA® provides meaningful and durable visual benefits for patients with RPE65-related disease, but long-term monitoring is essential to address its emerging ocular safety profile. Our data represent the first comprehensive pharmacovigilance review of LUXTURNA®, providing critical insights for clinical practice and post-marketing surveillance."

Adverse events • Journal • Review • Cataract • Gene Therapies • Genetic Disorders • Hematological Disorders • Inflammation • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa

Design of experiments in rAAV manufacturing: Optimization of plasmid ratio for better upstream yield (ESGCT 2024) - "Since the FDA approval of Luxturna in 2017, six more AAV-based therapies have entered the global market including Beqvez™ for the treatment of haemophilia B. The one-time treatment for severe haemophilia B either with Hemgenix® or Beqvez™ has a price tag in the US of $3.5 million per dose. An increase of up to 3x more vector genome titres across four common serotypes and two transgenes of different lengths was found, with productivity for some serotypes at >7E+14 VG/L of clarified cell culture. The method can be applied at the pre-discovery stage to identify capsids and transgenes with better productivity, or later during the preclinical stage to fine tune the plasmid amount for better empty:full ratios."

Hematological Disorders • Hemophilia • Hemophilia B • Rare Diseases

Can Gene Therapy Transform the Treatment Landscape of Posterior Segment Eye Diseases? A Comprehensive Review of Recent Advancements. (PubMed, Drugs) - "US Food and Drug Administration (FDA) approval of voretigene neparvovec (Luxturna®) for RPE65-associated IRDs validated the clinical viability of ocular gene therapy, while ongoing trials for AMD, DR, and other IRDs continue to expand the therapeutic landscape...Future directions in ocular gene therapy include the development of precision genome editing techniques, such as prime editing, miRNA-based regulation, and combinatorial approaches integrating gene therapy with stem cell transplantation or neuroprotective agents. As the field continues to evolve, addressing these challenges and optimizing gene therapy strategies will be crucial in translating the transformative potential of ocular gene therapy into clinical reality for patients with PSEDs."

Journal • Review • Age-related Macular Degeneration • Diabetic Retinopathy • Gene Therapies • Genetic Disorders • Inherited Retinal Dystrophy • Macular Degeneration • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • Transplantation

Understanding recombinant AAV production kinetics in HEK293 cells (ESGCT 2024) - "Because of this, the number of AAV gene therapy development pipelines have considerably increased in industry and academic groups worldwide since the approval of first AAV-based gene therapies (Glybera approved by EMA in 2012, Luxturna approved by FDA, 2017). This study will set up a framework for future analyses of the effect of different elements of AAV production process in the host cells, opening new possibilities for cell line engineering to improve AAV production. Moreover, we reflect on the need of reliable analysis methods for quick characterization of recombinant-AAV vectors in early stages of research and development, and we present technical challenges that need to be considered when quantifying viral genome titers in crude cell lysates using qPCR."

Gene Therapies

Results from LIGHT, a first-in-human AAV9-gene replacement therapy trial of HG004, in children and adults with RPE65-associated Leber’s congenital amaurosis (ESGCT 2024) - P1, P1/2 | "Although an adeno-associated virus serotype 2 (AAV2) gene therapy (voretigene neparvovec-rzyl; Luxturna) has been approved by the FDA and EMA in 2017 and 2018, respectively, AAV2 may not be an ideal vector to transduce the retinal pigment epithelial (RPE) cells than other serotypes such as AAV9. These three doses (25-, 15-, and 7.5-fold lower than the approved AAV2-hRPE65 gene therapy in the Phase 3 trial) in this LIGHT trial showed comparable results, suggesting that HG004 may potentially be a safer and more efficacious alternative treatment option for LCA2. HG004 is also being evaluated in a multi-regional clinical trial (NCT05906953) and granted both Orphan Drug Designation and Rare Pediatric Disease Designation by the U.S. FDA."

Clinical • First-in-human • P1 data • Gene Therapies • Inflammation • Inherited Retinal Dystrophy • Ocular Inflammation • Pediatrics • Retinal Disorders

One down but many more to go: the state of gene therapy for inherited retinal disease. (PubMed, Regen Med) - "Finally, we emphasize the need for improved regulatory frameworks and ethical considerations for gene-based therapies for IRD. The field now stands at a critical juncture, where the lessons of Luxturna can inform a more scalable, inclusive, and transformative future."

Journal • Review • Achromatopsia • Gene Therapies • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa

SNAC: A Single-Nuclei Atlas of Capsid Distribution in Nonhuman Primate Eye. (PubMed, Hum Gene Ther) - "Approved therapies such as voretigene neparvovec (Luxturna) and omnasemnogene abeparvovec (Zolgensma) rely on the tropism of natural AAV variants...Furthermore, the ranking of capsids by SNAC agrees with that from pre-established tissue sampling protocols. Our method promises to reduce the time, effort, and cost of accurate cell-type-specific profiling of AAV capsids."

Journal • Gene Therapies

A Patient Registry Study for Patients Treated With Voretigene Neparvovec in US (clinicaltrials.gov) - P=N/A | N=87 | Completed | Sponsor: Spark Therapeutics, Inc. | Active, not recruiting ➔ Completed

Trial completion • Gene Therapies • Inherited Retinal Dystrophy

Retinal gene therapy using epiretinal AAV-containing fibrin hydrogel implants. (PubMed, Sci Adv) - "However, adverse events (e.g., chorioretinal atrophy) have been reported in many patients receiving subretinal injection of Luxturna (voretigene neparvovec-rzyl) and experimental gene therapies...In contrast, epiretinal hydrogels degraded within days and led to broad transduction of RPE without atrophy or inflammation. This technology could advance gene therapy for retinal degenerations and other ocular or systemic disorders."

Journal • Gene Therapies • Inflammation • Ophthalmology

Pharmacoeconomic Profiles of Advanced Therapy Medicinal Products in Rare Diseases: A Systematic Review. (PubMed, Healthcare (Basel)) - "ATMPs for rare blood diseases, such as tisagenlecleucel and axicabtagene ciloleucel, were found to be cost-effective in a majority of studies, with incremental QALYs ranging from 1.5 to 10 per patient over lifetime horizon...Onasemnogene abeparvovec for spinal muscular atrophy (SMA) showed uncertain cost-effectiveness results, and voretigene neparvovec for retinal diseases was not cost-effective in 40% of studies, with incremental QALYs around 1.3 and high costs exceeding the WTP threshold set. ATMPs in treating rare diseases show promising economic potential, but cost-effectiveness varies across indications. Policymakers must balance innovation with system sustainability, using refined models and the long-term impact on patient outcomes."

HEOR • Journal • Review • Acute Lymphocytic Leukemia • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Gene Therapies • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Movement Disorders • Muscular Atrophy • Non-Hodgkin’s Lymphoma • Oncology • Ophthalmology • Rare Diseases • Retinal Disorders

Efficacy and Safety of Voretigene Neparvovec in RPE65-Retinopathy: Results of a Phase III Trial in Japan. (PubMed, Ophthalmol Sci) - "These results support the further applicability of VN to the Japanese population. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article."

Journal • P3 data • Gene Therapies • Inherited Retinal Dystrophy • Ophthalmology • Retinal Disorders

Genetic Therapies for Retinitis Pigmentosa: Current Breakthroughs and Future Directions. (PubMed, J Clin Med) - "Luxturna (voretigene neparvovec-rzyl), the first FDA-approved gene therapy targeting RPE65 mutations, represents a milestone in precision ophthalmology, while OCU400 is a gene-independent therapy that uses a modified NR2E3 construct to modulate retinal homeostasis across different RP genotypes...Moreover, QR-1123, a mutation-specific antisense oligonucleotide targeting the P23H variant in the RHO gene, is under clinical investigation for autosomal dominant RP and has shown encouraging preclinical results in reducing toxic protein accumulation and preserving photoreceptors. SPVN06, another promising candidate, is a mutation-agnostic gene therapy delivering RdCVF and RdCVFL via AAV to support cone viability and delay degeneration, currently being evaluated in a multicenter Phase I/II trial for patients with various rod-cone dystrophies. Collectively, these advances illustrate the transition from symptom management toward targeted, mutation-specific therapies, marking a..."

Journal • Review • Gene Therapies • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • NR2E3 • PRPF31 • USH2A

Gene therapy methods for rare ophthalmological diseases in the light of distributional justice-An overview (PubMed, Ophthalmologie) - "With the approval of Neparvovec (Luxturna®, Novartis) in 2018, a gene therapy for the treatment of retinitis pigmentosa and Leber's congenital amaurosis in RPE65 mutations, this innovation has also reached ophthalmology practice...Centralized data collection and negotiation structures increase efficiency and strengthen the position vis-à-vis manufacturers, while fund models such as the HIF promote the predictability of healthcare expenditure. In ophthalmology, questions arise regarding the prioritization of patient groups, intervention thresholds and the distribution of scarce resources, for example when treating the second eye after successful treatment of the first."

Journal • Review • Gene Therapies • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Rare Diseases • Retinal Disorders • Retinitis Pigmentosa

Retinal Viral Gene Therapy: Impact of Route of Administration on Serious Adverse Events-A Systematic Review. (PubMed, Clin Exp Ophthalmol) - "Subretinal injections show higher efficacy than intravitreal injections but are associated with more serious adverse events. Consistent adverse event patterns in humans and large animals highlight their predictive value for safety. There is a need for optimised delivery methods, refined dosing protocols, and improved post-treatment monitoring to improve safety and effectiveness in gene therapy."

Adverse events • Journal • Serious adverse event • Gene Therapies • Inflammation • Ophthalmology • Retinal Disorders

Short-Term Outcomes of Pediatric Patients With Mild Autosomal Recessive RPE65-Associated Retinal Dystrophy Treated With Voretigene Neparvovec. (PubMed, Transl Vis Sci Technol) - "Also, treatment at stages without profound retinal degeneration might lower the risk of fast-growing CRA. This study aids clinical decision-making in unclear cases by demonstrating that early treatment with voretigene neparvovec in mild RPE65-IRD provides functional benefits while minimizing the risk of fast-growing chorioretinal atrophy."

Journal • Infectious Disease • Inflammation • Inherited Retinal Dystrophy • Ophthalmology • Pediatrics