Colour blindness

Research begun in the 1990s is now coming to fruition with the initiation of the first retinal gene therapy trial for achromatopsia, and evidence suggests that the prospects for treating blue cone monochromatism is very promising, said Dominik Fischer MD, University Eye Hospital, Tübingen, Germany. There are three types of cones: the so-called blue cones, which have a peak sensitivity in the shorter visible wavelengths of light; the green cones, with a peak sensitivity at medium wavelengths; and the red cones, with a peak sensitivity in the longer wavelengths range, Dr Fischer told the 18th EURETINA Congress in Vienna, Austria. Achromatopsia is the dysfunction of all three types of cones and is sometimes called rod monochromacy. When only the blue cones are functional, the condition is called blue cone monochromacy; if only the medium-wave green cones are dysfunctional, it is a condition called deuteranopia, sometimes called Daltonism after the famous chemist who had and researched on the condition. Absence of the long-wave-sensitive red cones is a condition common to squirrel monkeys of central and south America. Achromatopsia is a rare autosomal recessive inherited retinal disorder with an incidence of approximately 1/30,000. It presents at birth or early infancy with nystagmus, photophobia, very poor visual acuity and colour vision and relies on luminance levels to distinguish between colours. The condition commonly (two out of three times) results from mutations in one of the genes for the alpha subunit or the beta subunit of cyclic nucleotide-gated channel (CNG) of the cone version of the cation channel that lies in the membrane of the cone receptors. Without this channel opening and closing, the cone cannot report to the brain when light that hits the cone. One-third of patients have mutations in other genes that also cause the condition. Achromatopsia does not appear to worsen with age, Dr Fischer noted. In detailed psychophysical tests using extended electrophysiology, and assessment of morphology by fundus autofluorescence and spectral-domain optical coherence tomography conducted in a population of patients with the condition, Dr Fischer and his associates found no correlation between the severity of morphologic and functional changes of the retina and age (Zobor et al, Invest Ophthalmol Vis Sci. 2017 Feb 1;58(2):821-832. doi: 10.1167/iovs.16-20427). Therefore, there is a wide window of opportunity for intervention with gene therapy. In knock-out mouse models of the condition, collaborating scientists from Munich developed a mouse model (knock-out mice) in which they switched off the CNGA3 gene. Around five years ago, the Tübingen scientists and their colleagues from Munich developed a gene therapy approach that they have used successfully in the mouse model. Experiments with the knock-out mouse model have shown proof of efficacy and proof of principle in gene therapy for the condition. In 2015, the scientists received approval from the relevant German authority and the ethics committee to commence the phase I dose-escalating clinical trial. A few weeks later, the first achromatopsia patient underwent the gene therapy treatment at the University Eye Hospital in Tübingen. BLUE CONE MONOCHROMACY Blue cone monochromacy (BCM), where only the blue cones are functional, is a very rare X-linked recessive inherited retinal disorder with an incidence of approximately 1/100,000. Like achromatopsia, the condition presents at birth or early infancy with nystagmus, photophobia and poor visual acuity. However, unlike achromatopsia, the condition appears to result in a gradual degeneration of cones over time, suggesting that there is a narrower window of opportunity for gene therapy in such patients. Nonetheless, a study in which the retinas of patients with blue monochromatism underwent adaptive optics imaging confirmed that human cones in patients with deletions in the red/green opsin gene array can survive in reduced numbers with limited outer segment material, suggesting potential value of gene therapy for BCM (Cideciyan et al, Hum Gene Ther. 2013 1; 24: 993–1006). Moreover, in an experiment involving adult red-green colour-deficient squirrel monkeys, gene therapy was sufficient to produce trichromatic colour vision behaviour. (Mancuso et al, Nature. 2009 Oct 8; 461(7265): 784–787). Dominik Fischer: dominik.fischer@med.uni-tuebingen.de

Tags: achromatopsia, deuteranopia, gene therapy, monochromacy