Gene therapy trials show

Inherited dystrophy

Gene therapy trials show promise for inherited retinal disease but challenges remain. Dermot McGrath reports

The past decade has seen an acceleration in the discovery of new disease genes and pathogenetic mechanisms underlying inherited retinal dystrophies (IRDs), thereby paving the way to a new era of targeted gene therapy to treat these degenerative diseases, according to Birgit Lorenz MD, PhD, FEBO, FARVO.

“IRDs are a large and heterogeneous group of neurodegenerative disorders that are associated with progressive visual dysfunction and are caused by mutations in any one of more than 220 different genes with a lot of genotypic and phenotypic variability. The last decade has seen a rapid increase in identifying genes enabled by next-generation sequencing (NGS) technology. At the same time, we have learned a lot about the pathophysiology of the retina as most of the genes are involved in formation, maintenance and functioning of the photoreceptors, both rods and cones,” said Prof Lorenz speaking at the World Ophthalmology Congress 2020 Virtual.

IRDs can be classified based on aetiology and describing pathophysiology: localised versus generalised disease, autosomal dominant or autosomal recessive, isolated or syndromic, rod versus cone loss, regional or longitudinal, she said.

“It is important to remember that the distribution of cones and rods are different throughout the retina and this distribution also influences the phenotype that we see. We therefore have to measure not only cone function for visual acuity but also rod function by dark adapted visual field and other specific tests,” she said.

Diagnostic tools for IRDs include imaging modalities such as fundus photography, fundus autofluorescence imaging (FAF) and optical coherence tomography (OCT).

Electrophysiology is also commonly used for diagnostics in conjunction with psychophysical testing for visual acuity, contrast sensitivity, kinetic and static perimetry, colour vision, and full-field stimulus threshold. In more advanced degenerative stages of IRDs ERG is often below detection level.

The fact that IRDs are highly heterogeneous with inter-individual variability makes them particularly challenging to diagnose and treat, noted Prof Lorenz.

“There is a need for more natural history studies of rare inherited retinal

degenerations to understand more about disease and stage specific inter-ocular differences. While long-term prospective longitudinal studies are required, we usually have only retrospective crosssectional data available. Furthermore, the value of short-term prospective studies often used by companies nowadays is questionable in slow, progressive diseases such as most IRDs,” she said.

Reviewing the progress of gene-based therapies in recent years, Prof Lorenz said that a major breakthrough was achieved in 2017 with the first-ever FDA approval of a gene therapy, Luxturna (Spark Therapeutics), for individuals with an inherited retinal disease due to mutations in both copies of the RPE65 gene.

Luxturna uses an adeno-associated virus vehicle to deliver normal copies of the RPE65 gene directly to the retinal pigment epithelial cells underlying the neuroretina via a subretinal injection.

The phase III trial that led to its approval showed significant improvements in navigation in dim light, full-field light sensitivity threshold, and visual field in the treated group, said Prof Lorenz.

“It was the results of the multiple luminance mobility testing (MLMT) that convinced the FDA and European authorities EMA to finally approve Luxturna as a gene therapy. However, we have got to remember that at least one paper has elaborated on the fact that the human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. So we have to really collect more data to determine when and if gene therapy can actually prevent progression of retinal degeneration,” she said.

The picture for choroideremia gene therapy is more mixed, with initial trials showing only modest improvements in visual acuity in a minority of patients.

“One of the challenges with choroideremia is that we are treating the fovea and injecting into the subretinal space with all the complexities that entails. There is debate about the preservation of the retina after the therapy with conflicting data: some groups say that there is continuous degeneration similar to the untreated eye while others claim there is better preservation in the treated eye,” she said.

Other clinical trials are also under way for Stargardt’s disease, achromatopsia, Usher syndrome and X-linked retinitis pigmentosa due to mutations in the RPGR gene.

Going forward, Prof Lorenz stressed the importance of obtaining objective, measurable data to show real clinical benefit from any gene therapy treatment.

“We are dealing with progressive disorders, with all that entails in terms of documenting natural course and treatment effect. We have new read-out parameters that are not all recognised at the moment by the health authorities, which have to be shown to be patient relevant. One of the critical questions right now is how early should we treat for optimal benefit. While early treatment in principle appears to be an advantage, there are specific surgical challenges especially for subretinal application at a very young age, so we need more data to improve our therapeutic strategies,” she said.