Dataset Information

The Role of the Human Visual Cortex in Assessment of the Long-Term Durability of Retinal Gene Therapy in Follow-on RPE65 Clinical Trial Patients.

ABSTRACT: Gene therapy (GT) has offered immense hope to individuals who are visually impaired because of RPE65 mutations. Although GT has shown great success in clinical trials enrolling these individuals, evidence for stability and durability of this treatment over time is still unknown. Herein we explored the value of functional magnetic resonance imaging (fMRI) as an objective measure to assess independently the longevity of retinal GT.Individuals with RPE65 mutations who underwent GT in their worse-seeing eye in a phase 1 clinical trial received a second subretinal injection in their contralateral eye in a follow-on clinical trial. Functional magnetic resonance imaging (MRI) was performed longitudinally to assess brain responses of patients with RPE65 mutations after stimulation of their most recently treated eye before and 1 to 3 years after GT.Seven participants with RPE65 mutations who were part of the follow-on clinical trial gave informed consent to participate in a longitudinal neuroimaging fMRI study.All participants underwent fMRI using a 3-Tesla MRI system and a 32-channel head coil. Participants' cortical activations were assessed using a block design paradigm of contrast reversing checkerboard stimuli delivered using an MRI-compatible video system.The primary parameters being measured in this study were the qualitative and quantitative fMRI cortical activations produced by our population in response to the visual task.Functional MRI results showed minimal or no cortical responses before GT. Significant increase in cortical activation lasting at least 3 years after GT was observed for all participants. Repeated measures analysis showed significant associations between cortical activations and clinical measures such as full-field light sensitivity threshold for white, red, and blue colors; visual field; and pupillary light reflex.Participants with RPE65 mutations showed intact visual pathways, which became responsive and strengthened after treatment. Functional MRI results independently revealed the efficacy and durability of a 1-time subretinal injection. The fMRI results paralleled those recently reported during the long-term clinical evaluations of the same patients. Results from this study demonstrated that fMRI may play an important role in providing complementary information to patients' ophthalmic clinical evaluation and has usefulness as an outcome measure for future retinal intervention studies.

SUBMITTER: Ashtari M

PROVIDER: S-EPMC5805133 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Publications

The Role of the Human Visual Cortex in Assessment of the Long-Term Durability of Retinal Gene Therapy in Follow-on RPE65 Clinical Trial Patients.

Ashtari Manzar M Nikonova Elena S ES Marshall Kathleen A KA Young Gloria J GJ Aravand Puya P Pan Wei W Ying Gui-Shuang GS Willett Aimee E AE Mahmoudian Mani M Maguire Albert M AM Bennett Jean J

Ophthalmology 20170223 6

<h4>Purpose</h4>Gene therapy (GT) has offered immense hope to individuals who are visually impaired because of RPE65 mutations. Although GT has shown great success in clinical trials enrolling these individuals, evidence for stability and durability of this treatment over time is still unknown. Herein we explored the value of functional magnetic resonance imaging (fMRI) as an objective measure to assess independently the longevity of retinal GT.<h4>Design</h4>Individuals with RPE65 mutations who ...[more]

PMID: 28237426

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Project description:Visual processing is strongly influenced by recent stimulus history, a phenomenon termed adaptation. Prominent theories cast adaptation as a consequence of optimized encoding of visual information by exploiting the temporal statistics of the world. However, this would require the visual system to track the history of individual briefly experienced events, within a stream of visual input, to build up statistical representations over longer timescales. Here, using an openly available dataset from the Allen Brain Observatory, we show that neurons in the early visual cortex of the mouse indeed maintain long-term traces of individual past stimuli that persist despite the presentation of several intervening stimuli, leading to long-term and stimulus-specific adaptation over dozens of seconds. Long-term adaptation was selectively expressed in cortical, but not in thalamic, neurons, which only showed short-term adaptation. Early visual cortex thus maintains concurrent stimulus-specific memory traces of past input, enabling the visual system to build up a statistical representation of the world to optimize the encoding of new information in a changing environment.SIGNIFICANCE STATEMENT In the natural world, previous sensory input is predictive of current input over multisecond timescales. The visual system could exploit these predictabilities by adapting current visual processing to the long-term history of visual input. However, it is unclear whether the visual system can track the history of individual briefly experienced images, within a stream of input, to build up statistical representations over such long timescales. Here, we show that neurons in early visual cortex of the mouse brain exhibit remarkably long-term adaptation to brief stimuli, persisting over dozens of seconds, and despite the presentation of several intervening stimuli. The visual cortex thus maintains long-term traces of individual briefly experienced past images, enabling the formation of statistical representations over extended timescales.

Dataset Information

The Role of the Human Visual Cortex in Assessment of the Long-Term Durability of Retinal Gene Therapy in Follow-on RPE65 Clinical Trial Patients.

Publications

The Role of the Human Visual Cortex in Assessment of the Long-Term Durability of Retinal Gene Therapy in Follow-on RPE65 Clinical Trial Patients.

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