Dataset Information

Retinal structure and function in achromatopsia: implications for gene therapy.

ABSTRACT:

Purpose

To characterize retinal structure and function in achromatopsia (ACHM) in preparation for clinical trials of gene therapy.

Design

Cross-sectional study.

Participants

Forty subjects with ACHM.

Methods

All subjects underwent spectral domain optical coherence tomography (SD-OCT), microperimetry, and molecular genetic testing. Foveal structure on SD-OCT was graded into 5 distinct categories: (1) continuous inner segment ellipsoid (ISe), (2) ISe disruption, (3) ISe absence, (4) presence of a hyporeflective zone (HRZ), and (5) outer retinal atrophy including retinal pigment epithelial loss. Foveal and outer nuclear layer (ONL) thickness was measured and presence of hypoplasia determined.

Main outcome measures

Photoreceptor appearance on SD-OCT imaging, foveal and ONL thickness, presence of foveal hypoplasia, retinal sensitivity and fixation stability, and association of these parameters with age and genotype.

Results

Forty subjects with a mean age of 24.9 years (range, 6-52 years) were included. Disease-causing variants were found in CNGA3 (n = 18), CNGB3 (n = 15), GNAT2 (n = 4), and PDE6C (n = 1). No variants were found in 2 individuals. In all, 22.5% of subjects had a continuous ISe layer at the fovea, 27.5% had ISe disruption, 20% had an absent ISe layer, 22.5% had an HRZ, and 7.5% had outer retinal atrophy. No significant differences in age (P = 0.77), mean retinal sensitivity (P = 0.21), or fixation stability (P = 0.34) across the 5 SD-OCT categories were evident. No correlation was found between age and foveal thickness (P = 0.84) or between age and foveal ONL thickness (P = 0.12).

Conclusions

The lack of a clear association of disruption of retinal structure or function in ACHM with age suggests that the window of opportunity for intervention by gene therapy is wider in some individuals than previously indicated. Therefore, the potential benefit for a given subject is likely to be better predicted by specific measurement of photoreceptor structure rather than simply by age. The ability to directly assess cone photoreceptor preservation with SD-OCT and/or adaptive optics imaging is likely to prove invaluable in selecting subjects for future trials and measuring the trials' impact.

SUBMITTER: Sundaram V

PROVIDER: S-EPMC3895408 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Publications

Retinal structure and function in achromatopsia: implications for gene therapy.

Sundaram Venki V Wilde Caroline C Aboshiha Jonathan J Cowing Jill J Han Colin C Langlo Christopher S CS Chana Ravinder R Davidson Alice E AE Sergouniotis Panagiotis I PI Bainbridge James W JW Ali Robin R RR Dubra Alfredo A Rubin Gary G Webster Andrew R AR Moore Anthony T AT Nardini Marko M Carroll Joseph J Michaelides Michel M

Ophthalmology 20131020 1

<h4>Purpose</h4>To characterize retinal structure and function in achromatopsia (ACHM) in preparation for clinical trials of gene therapy.<h4>Design</h4>Cross-sectional study.<h4>Participants</h4>Forty subjects with ACHM.<h4>Methods</h4>All subjects underwent spectral domain optical coherence tomography (SD-OCT), microperimetry, and molecular genetic testing. Foveal structure on SD-OCT was graded into 5 distinct categories: (1) continuous inner segment ellipsoid (ISe), (2) ISe disruption, (3) IS ...[more]

PMID: 24148654

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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

Retinal structure and function in achromatopsia: implications for gene therapy.

Purpose

Design

Participants

Methods

Main outcome measures

Results

Conclusions

Publications

Retinal structure and function in achromatopsia: implications for gene therapy.

Similar Datasets

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