Five years of gene therapy in Croatian ophthalmology – successes, challenges and perspectives

Abstract

Aim: Gene therapy has transformed the management of inherited retinal dystrophies (IRD), providing transformative solutions for conditions previously deemed untreatable. In 2017, the FDA approved voretigene neparvovec-rzyl (VN) (Luxturna, Spark Therapeutics) for RPE65-biallelic mutation-associated retinal dystrophies, followed by EMA approval in 2018. Without intervention, this condition typically progresses to blindness in the third or fourth decade of life. Voretigene neparvovec remains the only approved gene therapy for any IRD.

The aim is to evaluate the clinical outcomes, challenges, and future perspectives of five years of gene therapy in Croatia, focusing on the treatment of RPE65-associated IRDs at the Reference Centre for Inherited Retinal Dystrophies, University Hospital "Sveti Duh" in Zagreb.

Methods: Retrospective data analysis.

Results: Croatia initiated VN treatment in 2020, becoming the sixth national treatment center globally after the USA, Germany, Israel, France, and the UK. In January 2020, the Croatian Health Insurance Fund approved full reimbursement for VN, recognizing it as a high-cost treatment available exclusively at the University Hospital "Sveti Duh" in Zagreb.

Over five years, the center has treated 33 patients (61 eyes) aged between 1 and 66, establishing itself as the largest cross-border treatment hub worldwide. In addition to Croatia's citizens (11), patients from Belarus (1), Bulgaria (5), Montenegro (5), Bosnia and Herzegovina (1), Hungary (2), the Czech Republic (3), and Slovakia (5) were administered VN.

Eligibility is determined through a comprehensive pre-treatment assessment of visual function. Immunomodulatory therapy begins four days before the procedure, with the second eye treated 6–18 days later. Treatment outcomes demonstrated safety and efficacy, significantly improving scotopic vision across all age groups. Pediatric patients exhibited superior outcomes; however, functional rescue correlated more strongly with pre-treatment photoreceptor preservation than with age. No specific phenotypes or genotypes were associated with enhanced outcomes.

Adverse events were minimal and predominantly linked to surgical interventions, such as cataracts. Chorioretinal atrophy (CRA), a previously unreported adverse event during pivotal VN trials, was identified in post-marketing data. However, CRA events did not diminish the treatment’s overall benefits during the observed follow-up period.

Conclusions: The Croatian experience highlights substantial progress in overcoming challenges such as genotyping, ethical considerations, and logistical barriers. Five years of VN therapy in Croatia have demonstrated its safety and efficacy, particularly in pediatric patients. Looking forward, expanding access to gene therapy through international collaborations, advancing diagnostic tools for earlier detection, and exploring therapies for other IRDs will be crucial. Research into optimizing delivery techniques and mitigating long-term adverse events like CRA will further enhance outcomes. These efforts position gene therapy as a cornerstone of future IRD treatment within the framework of personalized medicine, with the potential to extend its benefits to a broader patient population.