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Ocular Gene Therapy

Head: Prof. Michalakis

The focus of the Ocular Gene Therapy research group is on i) the development of optimized viral vectors and related gene therapy approaches for hereditary retinal diseases, ii) the elucidation of genetic, molecular and cellular mechanisms of degenerative and neovascular eye diseases, and iii) the investigation of epigenetic gene regulation mechanisms in neuronal cells in the context of developmental and disease processes.

Subretinal injection of AAV gene therapy vectors

Using a fine injection cannula, the therapeutic recombinant adeno-associated virus (AAV) vectors are applied under the retina. The retina temporarily detaches from the retinal pigment epithelium and a subretinal bleb is formed (green, Fig. 1). Retinal cells, e.g. photoreceptors, which are located within the subretinal bleb can be transduced by conventional AAV vectors.

AAV subretinal Concept gene supplementation therapy
Figure 1. Illustration of subretinal injection of AAV gene therapy vectors. Figure 2. Concept of gene supplementation therapy using AAV vectors.

Gene supplementation therapy using AAV vectors

Recombinant AAV vectors carrying a genome with a gene expression cassette for expression of the target gene under the control of a cell type-specific promoter are applied by subretinal injection to reach directly the cell surface of the target cells (e.g. retinal pigment epithelial cells). There, the AAV vectors dock to surface receptors, are internalized in vesicles and traffic to the nuclear membrane. After release from the vesicles, the AAVs shuttle their single-strand genome into the nucleus, where it is converted into double-stranded DNA by intracellular processes, transcribed into RNA which can be translated into the target protein (Fig. 2). The mature protein can finally provide the missing function in the patients cells. The AAV genome remains in the cell nucleus without integrating into the host genome and can thus theoretically serve as a lifetime template for the missing gene product in non-dividing cells. Therefore, such AAV-mediated gene supplementation is considered to be a one-time administration.

Research Funding

Ongoing research projects are funded by the DFG in the Priority Program SPP2127, the Collaborative Research Center SFB1309 and by the National Institutes of Health (NIH, USA), among others.

Gene therapy for the treatment of achromatopsia

Several years ago, the Michalakis group at the Department of Pharmacy of the LMU, in close cooperation with Professor Martin Biel and the group of Professor Mathias Seeliger at the Eye Clinic Tübingen, was able to develop the first successful gene therapy approaches for CNGA3-related achromatopsia (ACHM2) and CNGB1-related retinitis pigmentosa (RP45). Achromatopsia is a rare inherited retinal disorder. Affected individuals are completely or partially color-blind. However, this should not be confused with the more common refractive error, the so-called red-green blindness, which is usually referred to as "color blindness". Retinitis pigmentosa refers to a retinal degeneration caused by inherited or spontaneous mutations which compromise the function of key proteins involved in function and/or homeostasis of photoreceptors. Based on successful proof-of-concept studies, three currently ongoing clinical programs have been initiated for CNGA3-related achromatopsia (ACHM2), CNGB1-related retinitis pigmentosa (RP45) and PDE6A-related retinitis pigmentosa (RP43). First results from the worldwide first phase I/II study on gene therapy for ACHM were published in April 2020 (press release of LMU, JAMA Ophthalmology 2020).

New gene therapy strategy against hereditary blindness

Retinitis pigmentosa is the most common form of hereditary blindness. Scientists from the Department of Pharmacy from the LMU Munich, in collaboration with Prof. Michalakis, have now used a gene therapy approach to compensate for the loss of defective genes in mice by specifically activating silenced genes with similar functions (press release from LMU in German).

Improved viral vectors for ocular gene therapy

Up until recently, there was no way to treat inherited blindness. In our days several gene therapy approaches designed to compensate for genetic defects in the retina are being developed. At present, the gene therapy vectors have to be injected directly under the retina (subretinally) which bare a certain risk of damaging the fragile retina. In addition, only a small part of the retina can be treated with such an injection. 

The Michalakis group and colaboration partners have now been able to develop optimized AAV vectors that bring their gene load to their target location, the light-sensitive photoreceptors, even if they are injected directly into the vitreous humor of the eye. Such a low-risk injection technique has been the clinical standard for years, for example in the treatment of macular degeneration. These novel AAV vectors now pave the way for the development of improved gene therapeutics  (Press release from LMU, EMBO Molecular Medicine).

Prof. Michalakis is author of more than 100 scientific publications. A complete list of publications can be found at PubMed

Members of the Ocular Gene Therapy research group

  Verantwortlich für den Inhalt: Prof. S. Michalakis