Two siblings, a brother aged 8 and a sister aged 3, affected the same form of hereditary retinal dystrophy, today can discern details, and move confidently in dimly lit environments, without fearing to trip over objects. They have regained important visual abilities after being treated with a gene therapy. The surgeries were performed in collaboration by the Ophthalmology unit of the Agostino Gemelli IRCCS University Hospital and Foundation and the Bambino Gesù Children’s Hospital, in the framework of a project launched in 2021 for the joint management of pediatric and adult patients suffering from hereditary retinal degeneration. The little girl who regained her sight is the youngest patient in Italy that received this treatment.

In 2021, the Italian Medicines Agency (Aifa) authorized the voretigene neparvovec gene therapy (trade name Luxturna) developed by Novartis for the treatment of rare forms of hereditary retinal dystrophy in adult and pediatric patients. These are the forms caused by the mutation of both copies (biallelic) of the RPE65 gene, responsible for the production of the key protein in the conversion of light into an electric signal in the retina.

The best-known hereditary retinal dystrophy is retinitis pigmentosa (RP), which affected in the early form – Leber’s congenital amaurosis – the two treated siblings. Retinitis pigmentosa can be caused by the mutation of about 100 genes involved in the vision mechanisms.

One of these genes is RPE65, whose mutations on the two copies of the gene are very rare and affect about 1 in 200,000 people worldwide. According to the prevalence studies, it is estimated that in Italy between 100 and 120 subjects are involved. Patients have problems such as poor night vision, narrowing of the visual field and may have a severe and progressive reduction of vision up to blindness. It is therefore a progressive disease, causing severe disability both in terms of school education and labor market opportunities.

The therapy consists of a single injection – “one shot” – into the subretinal space of both eyes of a functioning copy of the RPE65 gene. The healthy gene is carried inside the cells by an associated adenovirus, with modified genetic heritage, which acts as a vector. Once in the cells, the functioning copy of the gene is able to restore the patient’s vision in a meaningful and lasting way.

To access the treatment, specific clinical inclusion parameters have been established. The correct clinical characterization of retinal dystrophy and the identification of the RPE65 gene mutation through a genetic test are of fundamental importance, in order to make a correct diagnosis, assess the progress of the disease and set the correct therapeutic strategy.

In May last year, a framework agreement was signed between the Ophthalmology unit of the Agostino Gemelli IRCCS University Polyclinic Foundation, directed by Professor Stanislao Rizzo, and the Ophthalmology unit of the Bambino Gesù Children’s Hospital, directed by Professor Luca Buzzonetti, for the management of pediatric and adult patients with hereditary retinal degeneration. The goal is to improve the quality of healthcare provided to these patients by pooling resources and organizational skills. Through a diagnostic pathway by means of traditional protocols, patients are included in specific registers for possible therapeutic strategies. The approval of the first gene therapy for a specific mutation depending on hereditary retinal dystrophies – such as Leber’s congenital amaurosis and early onset retinitis pigmentosa, together with the identification of the Ophthalmology unit of Policlinico Gemelli as one of the Italian reference centers for related surgical procedure – led to the treatment of the first two pediatric patients affected by this pathology from the Bambino Gesù.

The two children are aged 8 and 3 and live in Sardinia with their parents who came to Italy from Senegal a few years ago for work reasons. The first patient receiving the gene therapy was the boy who has been under treatment at the Bambino Gesù Ophthalmology unit since he was 3 years old. The diagnosis of retinal dystrophy, confirmed by genetic tests, allowed him to be included in the register of patients eligible for voretigene neparvovec gene therapy immediately after approval by AIFA, when he was 7 years old. The therapy was administered to the right eye in October 2021 and to the left eye in December of the same year.

The post-operation follow-up, completed in February 2022, showed a significant improvement in all subjective visual parameters, i.e. visual acuity (ability to identify spatial details), visual field (ability to see peripherally) and twilight vision. The same applies to objective parameters through specific tests such as the FST (Full-Field Stimulus Testing, evaluating sensitivity of cones and rods, the retinal cells population that allows us to see).

The little sister, suffering from the same disease, is the youngest patient in Italy treated with gene therapy as she has just turned three. The first treatment took place in February 2022 and the second in June. For her, too, the follow-up completed in recent days has shown a significant recovery of sight.

A third patient at Bambino Gesù, aged 7, is currently candidate to the treatment.

“Gene therapy for inherited retinal degeneration – says Dr. Giancarlo Iarossi, contact person for retinal dystrophy at the Ophthalmology unit of the Bambino Gesù Children’s Hospital – represents the first concrete cure to prevent or correct the total decay of the visual function, and plays a fundamental role in future therapeutic strategies. Other forms of retinal dystrophy caused by various gene mutations are currently analyzed in advanced clinical trials. The hope of the operators involved is to continue this project aimed at adopting to our patients the most appropriate therapy according to current knowledge on retinal degeneration, and to extend it to other mutations in the future”.

“Operating very young patients and giving their sight back to them is something that goes beyond our professional lives and fully falls within the mission of the Gemelly and Bambino Gesù Hospitals, namely to treat people with very severe disabilities by using the results of the most advanced clinical research – says Professor Stanislao Rizzo, full professor of Ophthalmology at Università Cattolica and director of the Ophthalmology Unit of the A. Gemelli IRCCS University Hospital. – Retinitis pigmentosa is a terrible disease that in its most severe forms leads to blindness, and for which there was no effective therapy until recently. At last, even if for a limited number of patients, we can provide an effective treatment, resulting from the international scientific studies carried out in very few research and treatment centers in the world».