Research directions
Gene therapy for retinal disease
Retinal degeneration is the major cause of blindness in western countries. After glaucoma, diabetic retinopathy and age-related macular dystrophy (AMD), hereditary diseases are a leading cause of vision loss affecting particularly children and young adults. These last years, the growing efficiency and accessibility of genetic screening have revealed the wide genetic heterogeneity of retinal dystrophies (https://sph.uth.edu/retnet/sum-dis.htm#A-genes). However, most of these genetic defects are primarily affecting photoreceptors or retinal pigmented epithelium (RPE). We aim to develop new tools to better characterize, slow down or even stop retinal disease progression.
After having shown the efficacy of the lentiviral vector to target RPE (Kostic et al. 2003) and its limits to transduce photoreceptor cells (Grüter et al. 2005, Calame et al. 2011), we used this vector to restore visual function in two murine models of Leber Congenital Amaurosis (LCA) caused by RPE65 gene defect, an early-onset visual deficiency (Bemelmans et al. 2006, Kostic et al. 2011). We then evaluated the safety of this vector in non-human primates (Matet et al. 2017) and their effectiveness in targeting human RPE derived from iPS (Udry et al. 2020).
We are now focusing on vectors targeting photoreceptors in a model of ciliopathy (collaboration with prof Y. Arsenijevic (UNIL), prof C. Rivolta (UNIL) and prof D. Sharon (Hadassah-Hebrew University Medical Center).
Study of pupil light response as an indicator of retinal function
The pupil light response (PLR) is the result of the activation of three types of retinal photosensitive cells. While intrinsically photosensitive Retinal Ganglion Cells (ipRGCs) are important for the maintenance of the adaptation to ambient light, rods and cones bring additional temporal and spectral information. In human, different protocols varying intensity and wavelength of the light stimuli are being tested to isolate the PLR driven by these different cell types. However, due to the differences between human and mouse retina, the use of chromatic protocols in mouse models is not so easy to translate to human practice and vice versa.
To better understand the rod and cone participation in the PLR, we analyzed the PLR to a chromatic protocol in cone-only, rod-only or no-photoreceptor (no rods nor cones) mouse models. We showed that the initial dynamic of the PLR is largely influenced by rod and cone photoreceptors in these retinal mouse models (Kostic C et al. (2016)). We also examined the influence of retinal maturation on pupillary response in normal mice (Kircher et al. (2019)).
We then examined the initial dynamics of the PLR in humans in response to stimuli of different intensities and colors. We were able to highlight three parameters to quantify these dynamics which are influenced by cone, rod and ipRGCs photosensitive cells according to the light conditions (Kostic et al. (2021)).
These studies place the essential milestones for the continuation of our work focusing on the evaluation of pupillometry to characterize retinal dysfunction.
