Researchers Mark Success with Cone Cell Gene Therapy in Bid to Restore Visual Acuity in Achromatopsia
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Researchers mark success with cone cell gene therapy in bid to restore visual acuity in achromatopsia by Gearoid Tuohy Feature Bio-Ophthalmology esearchers in the US have reported Consequently, patients often describe the first successful cone-targeted being “dazzled” or “blinded' by bright light. R gene therapy restoration of visual Such photophobia may be somewhat acuity in a mouse model of achromatopsia. controlled through the use of red In a research report published in the coloured soft contact lenses or variously journal Nature Medicine, a single sub-retinal graded lenses using several different tints. administration of a virally delivered The contacts and additional lenses reduce transgene resulted in the rescue of both the amount of ambient light entering the the cone-mediated electroretinogram eye while maximising the intake of red (ERG) response and the visual acuity in a light to optimise rod photoreceptor cell mouse with the disease.Approximately one function. in 30,000 individuals are affected by achromatopsia, a disorder that can cause permanent central vision loss, for which no effective medical therapies exist. Achromatopsia, meaning Achromatopsia gained significant public awareness from the publication of a book “without colour”, is a by Dr Oliver Sacks titled, The Island of the disorder in which the Colorblind, in 1996. Dr Sacks' book, which was followed by a documentary film, individual is unable to recounted the inheritance pattern of achromatopsia among a small community distinguish colour due to a National Eye Institute, Institutes of Health on the Western Pacific island of Pingelap. Most of the present island inhabitants can deficient cone mediated Approximately 4X1010 AAV5 particles quantify physical movements of an animal's trace their ancestry to one or more containing the therapeutic construct were head as it tracks a visual stimulus across individuals that survived a typhoon in the ERG and typically sufferers injected sub-retinally into animal models of the field of vision. Quantification of the late 18th century. Estimates of achromatopsia. Of two batches of animals physical movement may then be analysed achromatopsia in the current Pingelap will have a severely one batch received the administration on to extract any correlation between treated population range from five per cent to 10 post-natal day 23 while a second batch and untreated animals. per cent with a carrier incidence of compromised visual acuity were injected on post-natal day 29. In the In the Florida study these assays approximatley 30 per cent. second batch the researchers conducted revealed that visual acuity had improved Achromatopsia, meaning “without additional sub-retinal injections into the only in those eyes that had received the colour”, is a disorder in which the The disorder in humans can arise from contralateral eye using an identical AAV5 therapeutic AAV5 injections. Mean visual individual is unable to distinguish colour mutations in the cyclic nucleotide-gated vector in which the therapeutic gene had acuity measurements between normal and due to a deficient cone mediated ERG and channel ≤-3 and guanine nucleotide ±- been replaced with a GFP (green treated eyes were not significantly typically sufferers will have a severely transducin (GNAT2). Drs John J Alexander flurorescent protein) reporter gene.The different demonstrating that visual acuity compromised visual acuity.There are two and William H Hauswirth, who are presence of the GFP reporter gene had been restored to levels observed in primary forms of the disorder – complete researchers at the Department of allowed the researchers to track both normal functioning animals. and incomplete achromatopsia. Complete Molecular Genetics and Microbiology at infectivity and expression levels enabling a Drs Alexander and Hauswirth remarked achromatopsia leaves patients with no real the University of Florida College of qualitative assessment of the procedure. that the study results “demonstrate the comprehension of the concept of colour Medicine, explained in their Nature The light adapted cone mediated ERG feasibility of targeting cones in order to resulting in a world which may appear Medicine report that “the GNAT2 mutant response was the primary measure of treat many of the most prevalent similar to a black and white photograph form of achromatopsia in humans, and efficacy used to evaluate test subjects one disorders threatening vision in humans. comprised of many different shades of grey. mice, results in a disruption of to two months after injection.The Potential target diseases include cone and Complete achromats typically have a visual heterotrimeric G-protein signalling, which research team found that over 90 per cent cone-rod dystrophies, late-stage retinitis acuity of 20/200 or less. In contrast, couples light-activated cone visual of treated animals responded to the pigmentosa (in which cones are lost after patients with incomplete achromatopsia pigments to the visual transduction therapy and of those that responded most rods have degenerated) and the retain a residual colour vision perception cascade”. positively approximately 90 per cent had exudative forms of age-related macular albeit profoundly impaired and often have a The Florida research team developed an light-adapted ERG amplitudes similar to degeneration and diabetic retinopathy (in less extreme visual acuity than that of the adeno-associated vector (AAV) delivery levels seen in normal wild-type animals. which macular cone loss accompanies complete form ranging from 20/60 to system to efficiently infect cone Interestingly, as the animals aged, the both macular edema and retinal 20/100. photoreceptor cells in the retina.The effect of the therapy appeared to persist neovascularisation).” The disorder may be identified in delivery vector was engineered with highly with almost 86 per cent of animals Each of these indications represent children by the presence of nystagmus, a specific promoter sequences which maintaining a recordable light-adapted extremely active fields of both academic wobbling or shaking of the eye coupled enabled constriction in the expression of ERG signal, 95 per cent of which appeared and commercial research spurred by the with abnormal light sensitivity.An ERG of the therapeutic gene to the cone cells to remain within the normal ERG range. large potential markets that presently have such patients will generally reveal an alone.This was achieved by use of a 2,100 In addition to measuring ERGs, and to few if any effective therapies available. abnormal photopic wave normal scotopic base pair section excised from the human ensure that an improved ERG was While gene therapy as a technology has ERG signal.As the disease impacts directly red/green opsin promoter.The promoter correlating with actual improvements in experienced somewhat of a roller coaster on the cone photoreceptors the main sequence was cloned into a plasmid vision, the research team used a standard in terms of clinical results, researchers are burden of vision falls on the rod upstream of the mouse cone ±-transducin visual behaviour test to determine any still confident that major successes may be photoreceptors which are ill-equipped to cDNA (GNAT2) and the combined changes in visual acuity.Visual acuity was close to hand. It is quite likely that the eye deal with the relatively bright illumination sequence was packaged into an AAV5 determined by measuring optomotor and several ophthalmic disorders may processed normally by the cones under vector. responses to a rotating sine-wave grating – soon become the beneficiary of long- scotopic conditions. essentially the researcher attempts to awaited clinical success. 33.