In vivo Analysis of Disease-Linked Mutations in Peripherin-2: Characterization of Pathomechanisms and Development of a miRNA-Based Gene Therapy for Autosomal Dominant Retinitis Pigmentosa

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Detection of light takes place in highly organized compartments of rod and cone photoreceptors called outer segments. The tetraspanin family member peripherin-2 is a glycomembrane-protein responsible for the structural integrity of rod and cone outer segments. Mutations in the peripherin-2 gene (PRPH2) are among the most common causes of degenerative retinal disorders which often lead to complete blindness. The majority of these mutations primary affects rod photoreceptors and results in autosomal dominant retinitis pigmentosa (adRP). By contrast, other mutations in PRPH2 lead to various cone specific diseases. So far the molecular mechanisms underlying this differential penetrance of single mutations in rods and cones remain unknown. Most of mutations in PRPH2 are missense-mutations located in exon 2. In this proposal we set out to characterize the pathomechanisms of disease-associated missense-mutations in exon 2 of peripherin-2 at the transcript and protein level. Consecutively, using a mouse model for adRP we plan to establish a miRNA based gene therapy to rescue the photoreceptor morphology and to prevent retinal degeneration. In summary, our study will help to decipher the pathomechanisms of peripherin-2 linked retinal disorders and to unveil the differential function of peripherin-2 in rods and cones. Finally, our results will provide an experimental platform for clinical studies on treatment of adRP.