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

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

Comparing Clinical Perimetry and Population Receptive Field Measures in Patients with Choroideremia

“… 31 This study used CHM as a disease model of photoreceptor degeneration and demonstrated strong positive relationships between SAP and pRF measurements. The current data are consistent with many previous fMRI studies of diverse patient populations 10 , 14 , 34 – 35 that have similarly demonstrated a link between clinical measures of visual function and cortical responses measured with fMRI.…”

“…Links between visual function, as measured clinically with SAP, and cortical representations, as measured through fMRI 34 and specifically pRFs, 14 have been reported for patients with cortical lesions. 14 and in patients with Leber's congenital amaurosis following retinal gene therapy.…”

Exon 13-skipped USH2A protein retains functional integrity in mice, suggesting an exo-skipping therapeutic approach to treat USH2A-associated disease

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The rapidly evolving state of gene therapy

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