The retina, transmits information from our visual world to the brain via the optic nerve. One of the important roles of the retina is to convert light into electrical signals, through phototransduction. The cells responsible for phototransduction are the photoreceptors, the rods (responsible for vision in dim light conditions) and the cones (responsible for colour and high acuity vision in bright light conditions. One of the main causes of blindness is rod/cone malfunction. This is often due to genetic mutations, leading to gradual rod and/or cone degeneration, and eventual partial or total and irreversible blindness. There are currently no available preventative treatments or new therapeutic interventions to cure patients suffering from these devastating conditions. Retinitis pigmentosa (RP) is a common form of hereditary photoreceptor dystrophy associated with progressive rod degeneration, leading to night blindness and loss of visual acuity. At later stages of the disease, cones degenerate as well, resulting in complete blindness. Therefore, there is a pressing need to develop novel approaches either for photoreceptor replacement or for reactivation of dysfunctional surviving photoreceptor by gene therapy (if performed at early disease stages).
Methods and hypothesis:
We develop artificial retinas (organoids) from human pluripotent stem cells (hPSCs). We isolate photoreceptors from these organoids and inject them in mouse retinas with photoreceptor dystrophies, with the goal to achieve integration of these healthy photoreceptors into the host retina, eventually restoring visual function. We have successfully achieved these goals using a cone-enriched population of photoreceptor precursors in a mouse model of RP, resulting in partial restoration of visual function assessed by behavioural and electrophysiological testing (Zerti et al. 2021). However, given the prevalence of rod degeneration in RP, our hypothesis is that transplantation of hPSCs-derived rods at early stages may lead to improved rod integration and function, while also protecting cones from degenerating at later stages. Moreover, we suggest that a combination of rod and cone transplantation may achieve optimal results at advanced degeneration.
Plan of work:
Here we propose to test this hypothesis in a mouse model of RP. The student will generate a novel hPSC reporter line, which will enable enrichment of cone and rod precursors, each one carrying a genetically encoded fluorescent marker of a different colour for easier identification once engrafted in the host retina. In one set of experiments, we will inject rods alone at early degeneration stages, with the goal of improving their integration into the host retina and protecting cones from later degeneration. In another set of experiments, we will inject a mixed population of rod and cone precursors at later stages of degeneration to see whether this approach improves photoreceptor integration at the advanced stages of RP.
Impact:
Using all the tools we have developed to generate homogenous populations of cone and rod precursors from hPSCs, perform successful cell transplantation and assess vision restoration using behavioural and electrophysiological approaches, this project will provide fundamental knowledge to establish the optimal conditions necessary for successful engraftment of stem cell-derived healthy photoreceptors to restore sight in devastating photoreceptor dystrophies.
How to Apply:
FURTHER DETAILS AND A GUIDE TO THE FORMAT REQUIRED FOR THE APPLICATION DOCUMENTS IS AVAILABLE AT https://www.ncl.ac.uk/research/transformative-neuroscience/studentship/ . Please read the information there before submitting your application. Applications not meeting these criteria may be rejected.
Applications should be made by emailing [Email Address Removed] with:
- a completed copy of the Application Form. A blank copy of the form can be found at: https://www.ncl.ac.uk/research/transformative-neuroscience/studentship/
- a CV (including contact details of two academic referees).
- a covering letter. This should explain your particular interest in the projects selected, and include any additional information you feel is pertinent to your application
- copies of your degree transcripts and certificates
- a copy of your passport (photo page).
- your English language certificate (IELTS or TOEFL certificate, where applicable)
Informal enquiries may be made to the supervisors.