LAUSR

Combined efforts in the field of gene therapy have generated exceptional advances recently by delivering opportunities to treat diseases unreachable by established therapies [1–3]. This has only been possible by conjoining the strength of several research areas including molecular biology, immunology, and human genetics, as well as clinical translation. To pinpoint the success of these collaborative achievements accumulated during 25 years of work the FDA approved the first adeno-associated virus (AAV)based gene therapy product for the treatment of a monogenic disorder (Leber congenital amaurosis-2, LCA2) in the end of 2017. The following year the treatment was likewise recommended for approval by the European Medicines Agency. LCA2 is a rare form of blindness caused by biallelic variations in the RPE65 gene, which encodes a fundamental enzyme of the visual cycle. This has without doubt consolidated the retina as a frontrunner of translational gene therapy and made memorable impression in the medical society [4], which in the end may bring gene therapy to a broader arena. Importantly, five additional gene therapy products for the treatment of spinal muscle atrophy, severe combined immunodeficiency, reduced production of hemoglobin (ßthalassemia), and B-cell cancers (based on two chimeric antigen receptor T-cell (CAR-T) therapies) have also been approved by the authorities [1]. This strongly implies the potential of gene-based medicines—not only for the treatment of inherited retinal dystrophies (IRDs), but also other incurable disorders. In the case of LCA2, the therapy is based on gene augmentation delivered by an AAV vector product entitled Luxturna (voretigene neparvovec-rzyl, Spark Therapeutics). Following a single subretinal injection of the AAV vector carrying a copy of RPE65, the LCA2 trials showed evidence of improvement in functional vision and increases in visual field and full-field light sensitivity [5]. Notably, the trials also documented safety and durability of the treatment [6]. As an outcome, the approval of Luxturna has formed an illuminated trajectory from the first proof-of-concept study to almost fifty gene therapy programs addressing other forms of IRDs with the use of a related treatment strategy [7–9]. In addition, significant efforts are being assigned to address new tasks, including advancements in vector design, improvements of gene transfer, delivery routes, robot-assisted injections, safety, durability, gene editing, mutation-independent therapeutic strategies, delivery of large genes, definition of the ideal window for gene therapeutic treatment, and robust outcome measures. Notably, development of combination gene therapy for treatment of multifactorial eye diseases, like age-related macular degeneration (AMD), which may require delivery of more than one gene product, has also attracted attention. Hopefully, with these blazingly fast developments, the field will be stimulated to advance these technologies and extend the initial achievement of retinal gene therapy.