Session on inherited retinal diseases and paediatrics featured talks addressing unmet needs, updates on outcomes of patients treated with voretigene neparvovec gene therapy, and new insights about select genetic diseases.
Marko Hawlina, MD, PhD (Slovenia) presented findings from longitudinal follow-up studies that highlight the importance of early diagnosis of IRDs in infants using ERG to rule out Leber’s congenital amaurosis or early cone rod dystrophy as well as for long-term follow-up of structural changes using autofluorescence and OCT to determine the natural disease course.
Discussing clinical follow-up of children with IRDs, Dr. Hawlina noted there are no existing common protocols nor published comprehensive transition programmes for these patients once they enter adulthood. To address that gap, ERN-EYE is developing a transition model in accordance with other European Reference
Networks.
Alejandra Daruich, MD, PhD (France) presented the latest outcomes of Luxturna (voretigene neparvovec) gene therapy in children with retinal dystrophy caused by biallelic mutations in the RPE65 gene. She noted that although consistent improvements in visual function have been demonstrated in the paediatric population, several challenges remain to be addressed. These include determining the optimal timing for intervention, minimising surgical trauma while optimising the target area, preventing chorioretinal atrophy (CRA), and assessing long-term efficacy and durability of the therapeutic effect.
A further discussion of CRA following Luxturna was the topic of the next talk by Bart LeRoy, MD, PhD (Belgium). He pointed out that three types of CRA have been identified, and they may have different causes. Therefore, it is important to avoid considering them as a single entity. Dr. LeRoy called attention to a recent publication presenting an expert consensus on the characteristics, etiology, and management of CRA in patients treated with Luxturna, suggested three possible causes – inflammation toxicity due to unbalanced stoichiometry, and toxicity due to AAV impurities – and described some do’s and don’ts for treating inflammation after gene therapy for RPE65-LCA.
Ana Rodriguez-Martinez, MD (United Kingdom) presented new genotype–phenotype correlations in CRB1-retinopathies, showing that disease severity can be influenced by the isoform and protein domain affected. She noted that variants that preserve the CRB1-B isoform were associated with milder phenotypes, namely macular dystrophy or cone-rod dystrophy, and variants that disrupt the transmembrane and intracellular domains were associated with Leber congenital amaurosis/early-onset severe retinal dystrophy.
Dr. Rodriguez-Martinez also shared the 24-month results of the natural history study from Moorfields Eye Hospital that showed visual acuity and retinal structure remained largely stable, whereas contrast sensitivity, macular sensitivity on microperimetry and tritan colour vision all declined. A child-friendly tablet test also detected the decline in contrast sensitivity function. She concluded that CRB1 gene therapy trials will need phenotype-stratified designs and functional endpoints that go beyond ETDRS visual acuity.
Isabelle Audo, MD, PhD (France) discussed hypotrichosis with juvenile macular dystrophy (HJMD) due to a CDH3 mutation. Interest in this very rare condition was prompted after it was diagnosed in a 7-year-old girl who had been referred for macular dystrophy. The encounter led to undertaking of a retrospective cohort study identifying patients with genetically confirmed HJMD being followed in the Reference Centre of Rare Diseases. Dr. Audo reviewed findings from that study.
The session concluded with a talk by M. Dominik Fischer, MD, PhD (UK) about a role for artificial intelligence (AI) in retinal dystrophies. He highlighted the potential to apply AI for enriching screening of clinical trial participants and to address the need for better clinical trial endpoints. Dr. Fischer presented findings from research done using AI to measure schisis cavity parameters in eyes with x-linked retinoschisis. He concluded that because of its benefits, including sensitivity to detect change, use of the AI-based metric as a study endpoint could reduce sample size requirements for future gene therapy clinical trials.
