Downstream effects of retinal gene therapy on the volume of the lateral geniculate nucleus (LGN): A functional and structural assessment

Abstract

Purpose : Retinal malfunctions are known to deteriorate downstream visual pathways. For example, optic tract, optic nerve and LGN in glaucoma patients significantly decrease in volume as compared to that of matched normal sighted controls (Lee JY et al., 2014). However, whether the deterioration is reversible has not been studied mostly due to the irreversibility of the retinal diseases. The recent advances in retinal gene therapy made possible the recovery of the retinal function. The purpose of the study was to find whether and how the regaining of the visual functions affects the volume of LGN.

Methods : Nine LCA2 patients underwent structural and functional MRI using a 3T system. Subjects received identical imaging protocol at baseline and 1 YR after their bilateral GT. To enable a precise measurement of the volume of LGN in MRI scans (Figure 1A), we applied a local 3D-edge detection algorithm that helped to visualize LGN (Figure 1B) and measure its volume. Visual stimulation was performed using checkerboard patterns with constant light intensity with a block design fMRI paradigm.

Results : The volume of LGN on the right side of patients’ brains before gene therapy was 165.1±38.1 mm³ (mean±SD). The volume of LGN increased to 179.8±41.2 mm³ (mean±SD) in one year after gene therapy. The increase in the volume was significant (P < 0.027, paired t-test). Interestingly, the increase in the volume of LGN correlated with the increase in functional activation of LGN area in response to visual stimuli (Figure 2). The LGN volumes on the left side of patients’ brains and on either side of the brains of normal sighted individuals are being processed.

Conclusions : Here we show through a combination of structural and fMRI that gene therapy in humans reverses the structural damage and re-establishes function to the main vision relay system in the brain.

This is a 2020 Imaging in the Eye Conference abstract.

 

Figure 1. A coronal slice of a patient’s brain with 0.8 mm resolution before (A) and after (B) local edge detection. Red arrow points at a triangle-shaped region with LGN.

 

Figure 2. A coronal slice of a patient’s brain showing functional activation (yellow to red) of LGN (at the cross-hairs) in response to flickering checkerboard before (A) and 1 year after (B) gene therapy. The statistical significance of the functional activation 1 year after gene therapy is much higher that of before the gene therapy (P < 0.005 vs. P < 0.05).