Long-term restoration of visual function in end-stage retinal degeneration using subretinal human melanopsin gene therapy

Silva, Samantha De; Barnard, Alun R.; Hughes, Steven; Ske., Tam; Martin, Chris; Singh, Mandeep S.; Barnea-Cramer, Alona; McClements, Michelle E.; During, Matthew J.; Peirson, Stuart N.; Hankins, Mark W.; MacLaren, Robert E.

doi:10.1073/pnas.1701589114

Cited by 69 publications

(67 citation statements)

References 43 publications

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“…RP is thought to affect 1.5 million people worldwide (37), with a prevalence ranging from 1 in 3000 to 1 in 4000, in certain populations (38,39). As a progressive IRD, RP is characterized by the degeneration of rod photoreceptor cells in the early stages of disease, followed by cone cell death.…”

Section: Inherited Retinal Diseasesmentioning

confidence: 99%

Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease

et al. 2019

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Inherited retinal diseases (IRDs) are a group of rare, heterogenous eye disorders caused by gene mutations that result in degeneration of the retina. There are currently limited treatment options for IRDs; however, retinal gene therapy holds great promise for the treatment of different forms of inherited blindness. One such IRD for which gene therapy has shown positive initial results is choroideremia, a rare, X-linked degenerative disorder of the retina and choroid. Mutation of the CHM gene leads to an absence of functional Rab escort protein 1 (REP1), which causes retinal pigment epithelium cell death and photoreceptor degeneration. The condition presents in childhood as night blindness, followed by progressive constriction of visual fields, generally leading to vision loss in early adulthood and total blindness thereafter. A recently developed adeno-associated virus-2 (AAV2) vector construct encoding REP1 (AAV2-REP1) has been shown to deliver a functional version of the CHM gene into the retinal pigment epithelium and photoreceptor cells. Phase 1 and 2 studies of AAV2-REP1 in patients with choroideremia have produced encouraging results, suggesting that it is possible not only to slow or stop the decline in vision following treatment with AAV2-REP1, but also to improve visual acuity in some patients.

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Section: Inherited Retinal Diseasesmentioning

confidence: 99%

Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease

et al. 2019

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“…Despite this, non-targeted and GC-targeted expression is still able to achieve a considerable degree of restoration. GC firing to light stimuli flows through to the visual cortex and an impressive amount of visual acuity and contrast sensitivity when measured by optomotor responses has been restored in mice as have light avoidance, freezing and object recognition behaviours [26][27][28][29][30][31][32][33][34], but see also [35]. Targeted expression has also photosensitized GCs in macaque and cultured human retina, enabling them to response directly to light stimuli [27,28].…”

Section: Introductionmentioning

confidence: 99%

Degenerated Cones in Cultured Human Retinas Can Successfully Be Optogenetically Reactivated

Kamar

Howlett

Klooster

et al. 2020

IJMS

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Biblical references aside, restoring vision to the blind has proven to be a major technical challenge. In recent years, considerable advances have been made towards this end, especially when retinal degeneration underlies the vision loss such as occurs with retinitis pigmentosa. Under these conditions, optogenetic therapies are a particularly promising line of inquiry where remaining retinal cells are made into “artificial photoreceptors”. However, this strategy is not without its challenges and a model system using human retinal explants would aid its continued development and refinement. Here, we cultured post-mortem human retinas and show that explants remain viable for around 7 days. Within this period, the cones lose their outer segments and thus their light sensitivity but remain electrophysiologically intact, displaying all the major ionic conductances one would expect for a vertebrate cone. We optogenetically restored light responses to these quiescent cones using a lentivirus vector constructed to express enhanced halorhodopsin under the control of the human arrestin promotor. In these ‘reactivated’ retinas, we show a light-induced horizontal cell to cone feedback signal in cones, indicating that transduced cones were able to transmit their light response across the synapse to horizontal cells, which generated a large enough response to send a signal back to the cones. Furthermore, we show ganglion cell light responses, suggesting the cultured explant’s condition is still good enough to support transmission of the transduced cone signal over the intermediate retinal layers to the final retinal output level. Together, these results show that cultured human retinas are an appropriate model system to test optogenetic vision restoration approaches and that cones which have lost their outer segment, a condition occurring during the early stages of retinitis pigmentosa, are appropriate targets for optogenetic vision restoration therapies.

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“…To meet these requirements we investigate the possibility of using innate behaviours instead of learned tasks. Visually evoked changes in exploratory behaviour have been applied to this problem (Cehajic-Kapetanovic et al, 2015;De Silva et al, 2017), but such tests are relatively low throughput and we were interested in the possibility of exploiting recent advances in understanding of rapid defensive behaviours as an alternative. Behaviourally salient visual stimuli, such as a looming dark spot (De Franceschi et al, 2016;Yilmaz and Meister, 2013) or a full field flash of light (Liang et al, 2015), can reliably trigger different behavioural responses.…”

Section: Introductionmentioning

confidence: 99%

Measuring vision using innate behaviours in mice with intact and impaired retina function

Storchi

Rodgers

Gracey

et al. 2019

Preprint

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Measuring vision in rodents is a critical step for understanding vision, improving models of human disease, and developing therapies. Established behavioural tests for perceptual vision, such as the visual water task, rely on learning. The learning process, while effective for sighted animals, can be laborious and stressful in animals with impaired vision, requiring long periods of training. Current tests that that do not require training are based on sub-conscious, reflex responses (e.g. optokinetic nystagmus) that don't require involvement of visual cortex and higher order thalamic nuclei. A potential alternative for measuring vision relies on using visually guided innate defensive responses, such as escape or freeze, that involve cortical and thalamic circuits. In this study we address this possibility in mice with intact and degenerate retinas. We first develop automatic methods to detect behavioural responses based on high dimensional tracking and changepoint detection of behavioural time series. Using those methods, we show that visually guided innate responses can be elicited using parametisable stimuli, and applied to describing the limits of visual acuity in healthy animals and discriminating degrees of visual dysfunction in mouse models of retinal degeneration.

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Long-term restoration of visual function in end-stage retinal degeneration using subretinal human melanopsin gene therapy

Cited by 69 publications

References 43 publications

Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease

Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease

Degenerated Cones in Cultured Human Retinas Can Successfully Be Optogenetically Reactivated

Measuring vision using innate behaviours in mice with intact and impaired retina function

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