Novel gene therapies
Our laboratory develops novel gene therapies for the treatment of inherited retinal diseases (IRD) such as retinitis pigmentosa and acquired retinal diseases such as age-related macular degeneration. While conventional treatments can slow the progression of the disease and alleviate the symptoms of acquired retinal diseases, they are unable to correct the underlying genetic defects of IRDs. Furthermore, the available treatments are recombinant antibodies or proteins that must be administered repeatedly (e.g., monthly or every two months) via intraocular injections, which places a significant burden on patients and their caregivers. We are therefore developing one-time, potentially curative gene therapies for IRDs or acquired retinal diseases. To facilitate preclinical development, our group develops human-relevant in vitro models, such as human retinal organoids. Some of theses projects are part of the DFG research unit for 'Ocular Gene Therapy'.
In addition to preclinical projects, our group has contributed vector candidates that are currently being tested in clinical trials. Prof. Dr. Stylianos Michalakis is scientific co-founder of VeonGen GmbH, a gene therapy company that develops novel gene therapies for the treatment of ABCA4 retinopathy (Stargardt disease) and retinitis pigmentosa.
Optimized viral vectors
Vectors based on adeno-associated viruses (AAV) have favorable properties for retinal gene therapy, such as broad tropism and high efficiency in the transduction of retinal cells, as well as a good safety profile.
Our lab develops new variants of AAV (e.g. AAV2.GL and AAV2.NN) with increased transduction efficiency and tailored cell tropism. We use directed evolution and rational design to improve the AAV capsid to enable higher efficiency and improve tropism and safety. In addition, we are investigating capsid-receptor interactions and AAV trafficking to improve our understanding of the AAV transduction mechanism and facilitate further improvements, such as the design of tailor-made affinities to certain receptors. Complementary studies aim to develop highly efficient and cell type-specific promoters.
A major disadvantage of AAV as a vector is its limited cargo capacity. To overcome this, we are working on technologies that enable an expansion of the cargo capacity of AAV, such as dual AAVs.
Role of TET enzymes and DNA demethylation in (retinal) neurons
The retina is a highly organized layer of specialized cells that converts light into electrical signals. To better understand the development of this complex system, our laboratory studies the epigenetics of retinal cells.
Epigenetic modifications such as DNA demethylation alter the transcription of certain genes and thereby influence cell development. TET enzymes play a crucial role in active DNA demethylation.
Our laboratory investigates the influence of TET deficiencies on the development of neurons and the retina using knockout models of iPSC-derived neurons, human retinal organoids, and mouse lines. This research is part of the Sonderforschungsbereich (SFB) 1309 – Chemical Biology of Epigenetic Modifications.
