Dataset Information

Genotype-dependent variability in residual cone structure in achromatopsia: toward developing metrics for assessing cone health.

ABSTRACT: Gene therapy trials for inherited photoreceptor disorders are planned. Anatomical metrics to select the best candidates and outcomes are needed. Adaptive optics (AO) imaging enables visualization of photoreceptor structure, although analytical tools are lacking. Here we present criteria to assess residual photoreceptor integrity in achromatopsia (ACHM).Two AOSLOs, at the Medical College of Wisconsin and Moorfields Eye Hospital, were used to image the photoreceptor mosaic of 11 subjects with ACHM and 7 age-matched controls. Images were obtained, processed, and montaged using previously described methods. Cone density and reflectivity were quantified to assess residual cone photoreceptor structure.All subjects with ACHM had reduced numbers of cone photoreceptors, albeit to a variable degree. In addition, the relative cone reflectivity varied greatly. Interestingly, subjects with GNAT2-associated ACHM had the greatest number of residual cones and the reflectivity of those cones was significantly greater than that of the cones in the subjects with CNGA3/CNGB3-associated ACHM.We present cone reflectivity as a metric that can be used to characterize cone structure in ACHM. This method may be applicable to subjects with other cone disorders. In ACHM, we hypothesize that cone numerosity (and/or density) combined with cone reflectivity could be used to gauge the therapeutic potential. As gene replacement would not be expected to add cones, reflectivity could be a more powerful AO-metric for monitoring the cellular response to treatment and could provide a more immediate indicator of efficacy than behavioral measures, which may take longer to change.

SUBMITTER: Dubis AM

PROVIDER: S-EPMC4235328 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Genotype-dependent variability in residual cone structure in achromatopsia: toward developing metrics for assessing cone health.

Dubis Adam M AM Cooper Robert F RF Aboshiha Jonathan J Langlo Christopher S CS Sundaram Venki V Liu Benjamin B Collison Frederick F Fishman Gerald A GA Moore Anthony T AT Webster Andrew R AR Dubra Alfredo A Carroll Joseph J Michaelides Michel M

Investigative ophthalmology & visual science 20141002 11

<h4>Purpose</h4>Gene therapy trials for inherited photoreceptor disorders are planned. Anatomical metrics to select the best candidates and outcomes are needed. Adaptive optics (AO) imaging enables visualization of photoreceptor structure, although analytical tools are lacking. Here we present criteria to assess residual photoreceptor integrity in achromatopsia (ACHM).<h4>Methods</h4>Two AOSLOs, at the Medical College of Wisconsin and Moorfields Eye Hospital, were used to image the photoreceptor ...[more]

PMID: 25277229

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Project description:Recent advances in regenerative therapy have placed the treatment of previously incurable eye diseases within arms' reach. Achromatopsia is a severe monogenic heritable retinal disease that disrupts cone function from birth, leaving patients with complete colour blindness, low acuity, photosensitivity and nystagmus. While successful gene-replacement therapy in non-primate models of achromatopsia has raised widespread hopes for clinical treatment, it was yet to be determined if and how these therapies can induce new cone function in the human brain. Using a novel multimodal approach, we demonstrate for the first time that gene therapy can successfully activate dormant cone-mediated pathways in children with achromatopsia (CNGA3- and CNGB3-associated, 10-15 years). To test this, we combined functional MRI population receptive field mapping and psychophysics with stimuli that selectively measure cone photoreceptor signalling. We measured cortical and visual cone function before and after gene therapy in four paediatric patients, evaluating treatment-related change against benchmark data from untreated patients (n = 9) and normal-sighted participants (n = 28). After treatment, two of the four children displayed strong evidence for novel cone-mediated signals in visual cortex, with a retinotopic pattern that was not present in untreated achromatopsia and which is highly unlikely to emerge by chance. Importantly, this change was paired with a significant improvement in psychophysical measures of cone-mediated visual function. These improvements were specific to the treated eye, and provide strong evidence for successful read-out and use of new cone-mediated information. These data show for the first time that gene replacement therapy in achromatopsia within the plastic period of development can awaken dormant cone-signalling pathways after years of deprivation. This reveals unprecedented neural plasticity in the developing human nervous system and offers great promise for emerging regenerative therapies.

Dataset Information

Genotype-dependent variability in residual cone structure in achromatopsia: toward developing metrics for assessing cone health.

Publications

Genotype-dependent variability in residual cone structure in achromatopsia: toward developing metrics for assessing cone health.

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