Genetic eye diseases usually result in a disorder of the retina and in many cases lead to significant limitations in vision, even blindness. Researchers from the NMI Natural and Medical Sciences Institute in Reutlingen, the Medical Faculty of the University of Tübingen and Boehringer Ingelheim recently published results from a study testing carrier viruses for gene therapies in a human retina-on-chip system in the renowned journal "Stem Cell Reports". With this novel system, future gene therapies for retinal diseases can be better developed.
Viral gene therapies for the treatment of genetic eye diseases
Gene therapies have great potential for ophthalmology in the treatment of genetic eye diseases such as retinitis pigmentosa, a pathological change in the retina. Basically, the retina consists of a complex yet orderly network of diverse cells, including the light-sensitive sensory cells, also called photoreceptors, which serve to perceive light. In the case of some genetic eye diseases, these photoreceptors are impaired in their function. Viral gene therapy can provide relief. The specially made therapeutic viruses are injected into the eye with a fine needle during treatment. However, the injected viruses do not produce disease, but transport genetic material into the cells of the eye. The way it works is similar to the mRNA vaccines made famous by the COVID 19 pandemic - the genetic material describes a blueprint that causes the cells at the injection site to produce a specific protein that is missing from the particular disease in the eye. In this way, the missing function of the protein can be restored in the patient.
Two treatment methods are currently available to deliver the viruses to the diseased cells: intravitreal injection, in which the viruses are injected into the vitreous body of the eye, and subretinal injection, in which the viruses are injected directly under the outermost boundary layer of the retina. The development of new therapeutic viruses is lengthy and costly in part because of the lack of suitable nonclinical models that have predictive power for the human eye.
"The combination of organ-on-chip with organoid technology enables an important step towards clinically relevant in vitro studies for the efficacy testing of gene therapies," said Prof. Dr. Peter Loskill, professor of organ-on-chip research at the Medical Faculty of the University of Tübingen and group leader at the NMI. Loskill and his team are developing small microfluidic platforms that allow living substructures of organs to be integrated into a controlled microenvironment, thus replicating the human organ outside the human body. Because these so-called chips replicate the natural, physiological microenvironment of the cells in the tissue, the cells and tissues integrated into them behave as if they were still in the human body and respond to a stimulus or drug.
To "artificially" replicate the human retina, Prof. Dr. Liebau's team at the Medical Faculty of the University of Tübingen produced a retinal pigment epithelium and retinal organoids from pluripotent stem cells - which can develop into all cell types in the body. These organoids are organ-like cell assemblies and consist of a variety of different cell types. By combining the microfluidic organ-on-chip platforms with the organoid technology, the researchers were able to infect the cells of the retinal organoid with viruses and produce a green fluorescent protein there. The retina chip used was designed so that the therapeutic viruses could be administered in a manner analogous to subretinal injection. In addition, the setup allowed long-term observation of the living cells and quantification of fluorescence, which is a crucial parameter for efficacy testing. Thus, the published data demonstrate the potential of stem cell-based organ-on-chip models as next generation screening platforms for future gene therapy studies.