UMC St Radboud

R.W.J. (Rob) Collin, PhD

The spectrum of inherited retinal dystrophies is clinically and genetically highly heterogeneous, with over 80 different causative genes identified to date. Recent successes in clinical trials using classical gene replacement therapy for Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) patients with RPE65 mutations have boosted the possibilities for developing therapies for inherited retinal dystrophies.

The general idea however is that each of the different genetic subtypes needs its own specific therapeutic approach. In my research group, we are currently developing therapy for one genetic subtype of retinal dystrophy, namely a severe form of LCA caused by a frequent intronic mutation in CEP290, present in up to 15% of all LCA patients.

This mutation is located in intron 26 of the CEP290 gene and creates a cryptic splice donor site that leads to the insertion of an aberrant exon in ~50% of the CEP290 transcripts, and causes premature termination of the CEP290 protein.

We have generated a transgenic mouse model that carries part of the human CEP290 gene including the intronic CEP290 mutation. This mouse model will be used to assess different therapeutic strategies to restore CEP290 function, that include subretinal delivery of viral vectors, and subsequent molecular (RT-PCR, Western blot, immunohistochemistry) and phenotypic (ERG, pupillometry, optokinetic responses) analysis methods.

In addition, we are currently generating and selecting additional animal models that will be used for pre-clinical therapeutic intervention studies in the near future.