Pharmacology for Natural Sciences

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Retinal gene therapy

Degenerative diseases of the retina are a major cause of blindness in the working age population and at present there is no treatment available. More than 200 genes causing inherited retinal diseases have been identified. In most cases a photoreceptor-specific mutation first leads to a functional impairment and subsequently to progressive degeneration and cell death of photoreceptors. Our current knowledge of the pathophysiological processes underlying retinal degenerations is quite limited.


Previously we established and characterized mouse models for Achromatopsia1-3 and Retinitis Pigmentosa4 by genetic ablation of the cone- (CNGA3) or the rod-specific (CNGB1) cyclic nucleotide-gated (CNG) channel, respectively. In both mouse models the respective affected photoreceptors accumulate high levels of cGMP, degenerate progressively and finally induce cell death.


Our current research focuses on the evaluation of AAV-mediated gene replacement therapy (Figure 1) as a treatment option for inherited retinal degenerations. We already successfully applied AAV-mediated gene therapy to restore vision in the Cnga3 knockout mouse model of Achromatopsia3 and the Cngb1 knockout model of Retinitis Pigmentosa5.

Figure AAV-mediated Gene TransferFigure 1. Cartoon illustrating the subretinal delivery of adeno-associated virus (AAV) vectors for the treatment of retinal degenerative diseases (A). Various promoters and AAV serotypes are available to achieve efficient and cell-type specific gene expression in rod (B) or cone (C) photoreceptors. IS, inner segments; ONL, outer nuclear layer; OPL, outer plexiform layer.

Another more general treatment option in retinal degenerations is to delay or inhibit degeneration and cell death of photoreceptors. Previously, we found that degenerating photoreceptors accumulate high amounts of the second messenger cGMP. Importantly, successful gene replacement therapy lowers cGMP to wild type levels (Figure 2). Our current research focuses on the analysis of the mechanisms leading to retinal degeneration and cell death with special emphasis on cGMP and its downstream targets. The overall goal is to advance our knowledge on the role of cGMP in retinal disease and in neurodegeneration and to identify potential targets for the pharmacological and/or genetic neuroprotection of rod and cone photoreceptors in retinal degeneration.

cGMP A3 GTFigure 2. Overview image of a retinal slice from a CNGA3 knockout mouse after AAV-mediated gene therapy stained for cGMP (green) and CNGA3 (red). The untreated (left) part with missing CNGA3 expression shows high levels of cGMP in cone photoreceptors. The treatment-border area (dashed rectangle) is also shown in higher magnification. In the treated part (right) AAV-mediated expression of CNGA3 lowered cGMP to levels that cannot be detected by cGMP-immunohistochemistry.



  1. Biel, M., et al. Selective loss of cone function in mice lacking the cyclic nucleotide-gated channel CNG3. in PNAS, Vol. 96 7553-7557 (1999).
  2. Michalakis, S., et al. Impaired opsin targeting and cone photoreceptor migration in the retina of mice lacking the cyclic nucleotide-gated channel CNGA3. Invest Ophthalmol Vis Sci 46, 1516-1524 (2005).
  3. Michalakis, S., et al. Restoration of cone vision in the CNGA3-/- mouse model of congenital complete lack of cone photoreceptor function. Mol Ther 18, 2057-2063 (2010).
  4. Hüttl, S., et al. Impaired channel targeting and retinal degeneration in mice lacking the cyclic nucleotide-gated channel subunit CNGB1. J Neurosci. 25, 130-138 (2005).
  5. Koch, S., et al. Gene Therapy Restores Vision and Delays Degeneration in the CNGB1-/- Mouse Model of Retinitis Pigmentosa. Hum Mol Genet Epub ahead of print July 16 (2012).