Prof. Dr. Stylianos Michalakis

Research methods: The group is working on the development of gene therapies based on adeno-associated virus (AAV) vectors for the treatment of ocular diseases, in particular focusing on the improvement of gene delivery vectors in order to better address the unmet need for gene therapies (retina/CNS). In addition, the group is interested in epigenetic mechanisms that control gene expression and neuronal differentiation, such as DNA demethylation by TET enzymes. We work with several in vitro models, including neurons and retinal organoids derived from induced pluripotent stem cells (iPSC). We are also working with mouse models to study the effects of specific knockout of genes of interest at the organism level. In addition to AAV vectorology and CRISPR/Cas-based methods, we use all state-of-the-art molecular biology, cell biology and biochemical methods in combination with various „omics" readouts. The group has access to confocal microscopes and devices for functional analysis of the retina.

Brief research description: I have a broad background and expertise in experimental ophthalmology, AAV vectorology, neuroscience, epigenetics, and pharmacology, with particular emphasis on retina and gene therapy of ocular diseases. Since two decades, my research involves the analysis of disease mechanisms involved in the pathobiology of inherited and acquired retinal diseases such as retinitis pigmentosa, achromatopsia, particularly, those forms caused by mutations in genes encoding cyclic nucleotide-gated channels (e.g. CNGA1, CNGA3 and CNGB1). A particular focus is the development and translation of gene therapies for these retinal diseases into clinical application. I am a founding member of the RD-CURE consortium (http://www.rd-cure.de), which successfully completed the world's first ocular gene therapy trial for CNGA3-linked achromatopsia and is currently conducting a phase IIb follow-up trial. RD-CURE also recently completed the first gene therapy trial for PDE6A-linked RP. In addition, I am co-PI of the NIH-funded R24 translational research program for gene therapy of CNGB1-linked RP. Finally, I am named inventor of two granted gene therapy patents and six patent applications.

Keywords: Gene therapy, retinal degeneration, aav vectors, epigenetics, tet enzymes

GSN students:

• Current: Grazia Giorgio, Anna Winkler, Sabrina Babutzka
• Graduated: Dr. Mirja Koch, Dr. Anna Sophie Geserich, Dr. Victoria Splith, Dr. Johanna Wagner

Selected publications:

Kandaswamy S#, Zobel L, John B, Santhiya ST, Bogedein J, Przemeck GKH, Gailus-Durner V, Fuchs H, Biel M, de Angelis MH, Graw J, Michalakis S.#, Amarie OV. # (2022) Mutations within the cGMP-binding domain of CNGA1 causing autosomal recessive retinitis pigmentosa in human and animal model. Cell Death Discov. 8(1):387

Li Y., Schön C., Chen C. C., Yang Z., Liegl R., Murenu E., Schworm B., Klugbauer N., Grimm C., Wahl-Schott C., Michalakis S.#, Biel M.# (2021) TPC2 promotes choroidal angiogenesis and inflammation in a mouse model of neovascular age-related macular degeneration. Life Sci Alliance 4(8), e202101047

Traube F. R., Özdemir D., Sahin H., Scheel C., Glück A. F., Geserich A. S., Oganesian S., Kostidis S., Iwan K., Rahimoff R., Giorgio G., Müller M., Spada F., Biel M., Cox J., Giera M., Michalakis S.#, Carell T.# (2021) Redirected nuclear glutamate dehydrogenase supplies Tet3 with alpha-ketoglutarate in neurons. Nat Commun 12, 4100

Pavlou M, Schön C, Occelli LM, Rossi A, Meumann N, Boyd RF, Bartoe JT, Siedlecki J, Gerhardt MJ, Babutzka S, Bogedein J, Wagner JE, Priglinger SG, Biel M, Petersen-Jones SM, Büning H#, Michalakis S.# (2021) Novel AAV capsids for intravitreal gene therapy of photoreceptor disorders. EMBO Mol Med. 13(4):e13392.

Fischer MD*, Michalakis S*, Wilhelm B, Zobor D, Muehlfriedel R, Kohl S, Weisschuh N, Ochakovski GA, Klein R, Schoen C, Sothilingam V, Garcia-Garrido M, Kuehlewein L, Kahle N, Werner A, Dauletbekov D, Paquet-Durand F, Tsang S, Martus P, Peters T, Seeliger M, Bartz-Schmidt KU, Ueffing M, Zrenner E, Biel M*, Wissinger B*. (2020) Safety and Vision Outcomes of Subretinal Gene Therapy Targeting Cone Photoreceptors in Achromatopsia: A Nonrandomized Controlled Trial. JAMA Ophthalmol. 138(6):643-651.