Retinal Disease Models for Development of Drug and Gene Therapies

Endpoint development trials are underway across the spectrum of retinal disease. New validated endpoints are urgently required for the assessment of emerging gene therapies and in preparation for the arrival of novel therapeutics targeting early stages of common sight-threatening conditions such as age-related macular degeneration. Visual function measures are likely to be key candidates in this search. Over the last two decades, microperimetry has been used extensively to characterize functional vision in a wide range of retinal conditions, detecting subtle defects in retinal sensitivity that precede visual acuity loss and tracking disease progression over relatively short periods. Given these appealing features, microperimetry has already been adopted as an endpoint in interventional studies, including multicenter trials, on a modest scale. A review of its use to date shows a concurrent lack of consensus in test strategy and a wealth of innovative disease and treatment-specific metrics which may show promise as clinical trial endpoints. There are practical issues to consider, but these have not held back its popularity and it remains a widely used psychophysical test in research. Endpoint development trials will undoubtedly be key in understanding the validity of microperimetry as a clinical trial endpoint, but existing signs are promising.

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Establishment of retinal disease models using non-human primates and its strategy for drug discovery

Folia Pharmacologica Japonica ◽

10.1254/fpj.152.139 ◽

2018 ◽

Vol 152 (3) ◽

pp. 139-146

Author(s):

Masamitsu Shimazawa ◽

Hideaki Hara

Keyword(s):

Drug Discovery ◽

Retinal Disease ◽

Disease Models

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A demonstration of cone function plasticity after gene therapy in achromatopsia

10.1101/2020.12.16.20246710 ◽

2020 ◽

Author(s):

Mahtab Farahbakhsh ◽

Elaine J. Anderson ◽

Andy Rider ◽

John A. Greenwood ◽

Nashila Hirji ◽

...

Keyword(s):

Gene Therapy ◽

Visual Cortex ◽

Neural Plasticity ◽

Treatment Strategies ◽

Retinal Disease ◽

Preliminary Evidence ◽

Gene Therapies ◽

Cone Function ◽

Child Friendly

AbstractAchromatopsia (ACHM) is an inherited retinal disease characterised by complete loss of cone photoreceptor function from birth. In recent years, gene therapies have successfully been used to induce signal processing in dormant cones in animal models of ACHM, with greater functional benefits for younger animals. With several completed or on-going clinical trials of gene therapy for ACHM, preliminary evidence suggests that effects on visual function in adults with ACHM may be subtle. Given the known constraints of age on neural plasticity, it is possible that gene therapy earlier in life will have a greater impact. Sensitive, child-friendly tests of cone function are therefore needed to facilitate the optimisation of these treatment strategies. Here, we present a new method that leverages a multimodal approach, linking psychophysical estimates of cone function to cone-mediated signals in visual cortex, measured using fMRI. In a case study of two children with ACHM undergoing gene therapy, we find individual differences in recovery of cone function over time, with one child demonstrating strong concurrent evidence of improved cone function, and retinotopically organised responses in visual cortex to cone-selective stimuli. Integrated fMRI and psychophysical measures may provide insight into the utility of new sight-rescuing therapies at different stages of human development.

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