Central visual pathways affected by degenerative retinal disease before and after gene therapy

Area of Science:

• Neuroscience
• Ophthalmology
• Genetics

Background:

• Leber congenital amaurosis (LCA) is a rare, inherited retinal disease causing severe vision loss.
• Gene therapy targeting RPE65 mutations (LCA2) shows promise but its effects on central visual pathways are poorly understood.

Purpose of the Study:

• To investigate how LCA2 disease and gene therapy impact visual signal transmission in the brain using functional MRI (fMRI).
• To assess changes in subcortical and cortical visual structures following retinal gene therapy.

Main Methods:

• Functional MRI (fMRI) was employed to measure brain activity in response to visual stimuli before and one year after gene therapy in LCA2 patients.
• Visual activation patterns were analyzed in response to flickering checkerboards, comparing LCA2 patients to controls.

Main Results:

• LCA2 patients exhibited heightened superior colliculus and diminished lateral geniculate nucleus (LGN) activity, indicating a shift towards the retinotectal pathway.
• Gene therapy led to increased fMRI responses in the LGN and primary visual cortex, suggesting partial restoration of the geniculostriate pathway.
• Post-treatment LGN activity correlated with improved light sensitivity, demonstrating a link between restored visual pathway function and clinical outcomes.

Conclusions:

• LCA2 disease involves a compensatory shift in visual processing to the retinotectal pathway.
• Retinal gene therapy can partially restore visual transmission via the geniculostriate pathway, correlating with functional vision improvements.
• Findings may inform the development of new therapeutic and rehabilitation strategies for low vision patients.