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Modeling and treating retinal degenerative disease

Periodic Reporting for period 4 - REGENETHER (Modeling and treating retinal degenerative disease)

Reporting period: 2020-06-01 to 2020-11-30

Adeno-associated virus (AAV) vector-based gene therapy has showed early promise in clinical trials. Different AAV capsid pseudotypes can be used to package the therapeutic transgenic cassette, each with its own transduction profile. Currently, the efficiency of AAV capsid serotypes in small animal models is used to select AAV capsid serotypes for clinical trials. There has been progress in improving gene therapy for eye diseases in rodents and today we know that small animal studies are not predictive of human outcome in gene therapy. Furthermore, non-human primates utilized as pre-clinical animal models show no signs of disease, rendering them unsuitable for efficacy testing. In this project we attempted to circumvent these constraints in translational gene therapy by developing non-human primate models of retinal degeneration and generating AAVs responding to a clinical new and original gene therapies.
We met our set objectives of setting up a methodology to screen for successful viral variants in human post-mortem retinas. We further developed a translational pipeline that allow us to test the efficacy of restorative therapies from mice to in vitro human cell models to in vivo non-human primates. Along the way, we assessed the immune status of macaques and the contribution of this factor to gene therapy doses and routes of administration used for retinal gene therapy.
REGENETHER aims to go beyond the current methods in building a pre-clinical testing platform for gene and cell therapies in the retina. Creation of a nonhuman primate model with retinal degenerative phenotype will push the boundaries of our understanding of disease and how vectors act in such a system both in terms of delivery and function. Beyond what was assessed in the initial stages of the project we have also evaluated implementation of surgical techniques to add to the versatility of the primate approach in view of the therapeutic to be tested. Such animal models will enable to go further than the standard pre-clinical assessments (pharmacology and toxicity studies) and open the doors to functional tests. Such tests are essential to reveal potential efficacy of treatments aiming to fight blindness in humans and yield biological insight into disease mechanisms outer retinal degeneration.

We created new AAV capsids adapted to human retina using and ex vivo selection paradigm. We have generated a large amount of data on the selection process thanks to the implementation of next generation sequencing. These new datasets allowed us to better understand the process and the numerical aspects of the experimental parameters. We hope this data will allow machine learning backed models for this type of selection after the end of the project. We thus need to await further, in order to fully measure the impact the project will have at the higher levels. However on a smaller scale, the progress has been up to our expectations and we have met the technical milestones that pave the way to achieve the broader objectives
The bioengineering strategy using human samples can also be applied to other organs and can be a brilliant alternative to the state of the art xenograft models.