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In vivo genome editing to treat inherited retinal dystrophies - how close are we to realization?

Extraordinary CRTD Seminar

Date:23.05.2017, 14:00 - 15:00
Speaker: Prof. Dr. Dr. med. vet. Knut Stieger (Professor of Experimental Ophthalmology, Faculty of Medicine, Justus-Liebig-University Giessen)
Location: CRTD, auditorium left
Host: Dr. Volker Busskamp

About the research of Prof. Stieger:

Inherited retinal dystrophies are a group of disorders with a prevalence of 1 in 3-4000 people. Owing to the complexity of the visual system, several hundred proteins are uniquely expressed in the retina, and mutations in over 200 genes have been associated with retinal dystrophies.

Targeted genome editing may represent an alternative method to treat retinal dystrophies by correcting the disease-causing mutation within the genome in order to restore the “wild type” DNA sequence of a given gene, enabling the cell to produce what is needed to have optimal phenotypic outcome. Genome editing is based on the cells own capacity to repair DNA double strand breaks (DSB), which are the most dangerous form of DNA damage that can occur to a cell.

DSBs are repaired either by sticking the DNA ends together in a mechanism called nonhomologous end-joining (NHEJ), or by use of the sister chromatid as template DNA via homology directed repair (HDR). A special form of HDR represents the mechanism called micro-homology mediated endjoining (MMEJ).

The idea of using targeted genome editing to repair disease causing mutations in the retina in vivo is comparatively young. This approach aims at treating the mutations directly in retinal cells in situ. Vehicles for in vivo gene transfer exist in form of virus based vectors, such as adeno-associated virus (AAV) vectors. The major drawback here is the post-mitotic state of the cells, which very likely hinders efficient genome editing, and the absence of screening and selection possibilities.

In this presentation, I will focus on the different DNA repair mechanisms, the current state of the art tools for genome editing and the particularities of the retina and photoreceptors with regard to in vivo therapeutic approaches. Finally, current attempts in the field of in vivo genome editing in the retina will be discussed and future directions of research identified.

5 most important publications:

1.     Song F, Stieger K. (2017) Optimizing the DNA donor template for homology directed repair of double strand breaks. Mol Ther Nuc Acid, advanced online publication

2.     Mⁿller B, Wagner F, Lorenz B, Stieger K. (2017) Organotypic Cultures of Adult Mouse Retina: Morphologic Changes and Gene Expression. Invest Ophthalmol Vis Sci. 58(4):1930-1940.

3.     Giers BC, Klein D, Mendes-Madeira A, Isiegas C, Lorenz B, Haverkamp S, Stieger K. (2017) Outer Plexiform Layer Structures Are Not Altered Following AAV-Mediated Gene Transfer in Healthy Rat Retina. Front Neurol. 23;8:59

4.     Yanik M, Mⁿller B, Song F, Gall J, Wagner F, Wende W, Lorenz B, Stieger K (2017) In vivo genome editing as a potential treatment strategy for inherited retinal dystrophies. Prog Ret Eye Res. 56:1-18

5.     Wimmer T, Lorenz B, Stieger K (2016) Quantification of the vascular endothelial growth factor with a bioluminescence resonance energy transfer (BRET) based single molecule biosensor. Biosens Bioelectron 86:609-15

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