Achromatopsia: Exploring nature and plasticity of vision in the absence of functional cones

• Applicant: Professor Dr. Michael Hoffmann
• Subject Area: Ophthalmology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 262033421

Achromatopsia is characterized by a dysfunction of all cone photoreceptor types in the retina. As in many forms of inherited retinal disorders, mutations of a single gene, predominantly CNGA3 or CNGB3, are sufficient to cause the disease. Since photoreceptors stand at the very beginning of vision, a functional loss has severe consequences for all downstream parts of the visual pathways. Here, we set out to assess the effects caused by dysfunctional cones on different levels of vision to specify the interplay of pathophysiology and neural plasticity in a comparative approach.We will study the effects of AC in human patients and in a mouse model, which allows us to ex-plore the potential for a partial or full reversal of the AC phenotype following gene replacement therapy. The proposal profits from the fact that curative gene therapy in achromatopsia (AC) is most advanced as highlighted by our recent successful restoration of vision in a respective mouse model [cnga3-/-] (Michalakis, et al., 2010). It is therefore likely to be established in the future for human applications. While this primary work focused on the correction of the genetic defect, we are here investigating the implications of a therapeutic restoration at the photoreceptor level on the visual system in its entirety. Specifically, our research questions concern (i) the state of the native visual system in AC, (ii) the plasticity and reorganisation of the brain regions involved, (iii) the de-pendence of visual system state and plasticity on modifying factors like age and individual geno-type, and (iv) the relevance of neural plasticity for visual function and for restoration of visual func-tion in the mouse model. These investigations will be conducted largely in parallel in man and mouse (the latter offering the comparison of untreated & treated states) with combined behavioural and physiological techniques, comprising advanced imaging (mainly MRI/fMRI) and non-invasive electrophysiology.In a more general view, this study in AC will help to estimate the impact of modifying factors and plasticity on treatment success in visual system disorders. Its outcome is expected to aid the opti-misation of upcoming retinal gene therapeutic interventions in order to facilitate individualized gene therapy of human AC. Specifically, this includes the choice of biomarkers for detection and follow-up of therapeutic success, and the establishment of diagnostic and general criteria for patient se-lection in upcoming trials. Furthermore, the comparative, detailed investigation of AC is expected to produce fundamental insights into the interplay of pathophysiology and plasticity in the mammalian visual system.

• DFG Programme: Research Grants