DiagnosysFST continues to be an important diagnostic tool to quantitatively evaluate the efficacy of breakthrough gene therapies for inherited retinal degeneration.
We recently witnessed a new breakthrough in gene editing. This time it’s for CEP290-associated inherited retinal degeneration (IRD), thanks to the BRILLANCE study sponsored by Editas Medicine. In a recent paper published in the New England Journal of Medicine, researchers reported successful in vivo gene editing in a clinical trial that resulted in productive therapeutic levels of the CEP290 protein expression and enhanced cone photoreceptor function. This development comes after the FDA approval in 2019 of LUXTURNA, (a trademark of Spark Therapeutics, Inc.,) famously the first-ever gene therapy for RPE65-associated IRD.
Both genes, RPE65 and CEP290, are associated with Leber’s congenital amaurosis (LCA), a childhood genetic retinal blindness. They are among at least 23 genes identified that, when mutated, can lead to LCA. Affected infants and young children show difficulties navigating or recognizing objects and faces in dimly lit environments. Certain subjects treated with LUXTURNA have been reported to have recovered sufficient visual function to see illuminated dials, reflections, tree branches, windows, and faces. Other subjects can recognize color or have been able to walk independently at night.
These breakthroughs in retinal gene therapies were supported by psychophysical tests called full-field stimulus threshold tests, or FST. These tests are at the core of baseline, post-treatment, and longitudinal tests. They provide an important quantitative basis upon which gene therapy clinical trials are evaluated. A review of clinical treatments for RPE65-associated retinal dystrophy published in February 2021 in Molecular Therapy lists eight RPE65 clinical trials, all of which used visual psychophysics to evaluate efficacy of the outcomes. FST is valued for its ability to produce quantitative assessments, especially in children and patients with severe vision loss and poor visual fixation abilities.
In this most recent study of CEP290 gene editing, dark-adapted FST was used to evaluate the retinal sensitivities of the participants to blue, red, and white light. The researchers reported that six out of the fourteen participants treated showed meaningful improvement in cone photoreceptor functions as assessed with the use of FST. The magnitude of improvement appeared to be related to the level of dysfunction at baseline, in that the greatest change was observed in participants with worse sensitivities. The researchers indicated that follow-up over a longer period, including using FST, will be needed to evaluate long-term risks associated with off-target effects of gene editing.
FST guidelines were updated in January 2024 based on the joint work of the International Society for Clinical Electrophysiology of vision (ISCEV) and the Imaging and Perimetry Society (IPS). The guidelines promote the consistency of testing and reporting and the convergence of FST methods. FST involves the use of a ganzfeld stimulator to deliver full-field flashes of light.