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Bild einer IAV Infektion in der menschlichen Lunge, in der ein Alveolarmakrophage eine Virus-infizierte Zelle efferozytiert. Copyright: A. Hocke/Charité



Kick-off for three new projects using human 3D-models and thereby reducing the use of animals

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Charité 3R is funding three new research projects that use human tissue or stem cells as starting point to simulate certain aspects of human pathophysiology and thereby replace or reduce animal testing in their research. From a total of 34 proposals, 14 external reviewers have now selected three research projects for further funding. The impressive number of submitted applications illustrates the great importance that human 3D models now have in research at Charité, therefore, the decision was not an easy one for the experts.

In the project "Modeling defective Ras signaling in human cerebral organoids - Towards a therapy for the severe neurodevelopmental rasopathy SynGAP syndrome", the researchers aim to develop a human cell-based system to support drug development for the so-called SynGAP syndrome, a rare genetic disorder caused by a mutation on the SYNGAP1 gene. Since the SynGAP1 protein modulates the so-called "Ras signal transduction" and thus significantly influences the communication between nerve cells and synapses, mutations of this gene lead to severe neurological developmental disorders with mental retardation, autistic traits and seizures. Prof. Sarah Shoichet (Neuroscience Research Center), Dr. Nils Rademacher (German Center for Neurodegenerative Diseases) and Dr. Agnieszka Rybak-Wolf (Max Delbrück Center for Molecular Medicine & Berlin Institute for Medical Systems Biology (BIMSB)) want to identify genetic and pharmacological factors that have the potential to restore neuronal Ras activity in neurons of patients with SynGAP syndrome. To do this, they constructed a fluorescent sensor for Ras activity as a first step. In the next step, the researchers plan to differentiate cerebral organoids from human pluripotent stem cells and combine the Ras sensor with microelectrode arrays and calcium imaging to study the effects of impaired Ras signaling. The goal is to provide a human cell-based system for testing potential drugs for SynGAP syndrome while reducing the number of animals needed to understand disease mechanisms.

The aim of the project "A human stem cell derived neuronal network for high-throughput cognitive drug screening" is to develop a human induced pluripotent stem cell (iPSC)-derived model for high-throughput screening of compounds that are candidates for treatment of Alzheimer's disease. Approximately 50 million people worldwide are affected by dementia, at an annual cost of 1 Billion Euros. Clinical trials have repeatedly failed, possibly because the existing mouse models in this field can only be transferred to humans to a limited extent. To address this problem, Dr. Camin Dean of the German Center for Neurodegenerative Diseases at Charité wants to develop models based on human cells. Her focus is on synapses, the connections between nerve cells in the brain that are weakened in early stages of dementia. Together with her research group, the scientist wants to test substances that strengthen the synapses and could be used to treat dementia and other neurological disorders. These human models could prove helpful for drug testing while reducing the number of animal experiments.

In the project "An autologous model of the adaptive immune response in human lung organoids: Targeting infection with influenza-specific T-cells", the researchers want to develop a human lung model from the lung tissue of a patient with the specific immune responses of this same patient - in other words, a so-called human, immune-competent and autologous lung model. This model will be used to test the efficacy and safety of a therapy using the patient's own T-cells. This T-cell therapy acts specifically against influenza viruses and can be used to treat influenza infection. This approach uses the patient's own T cells isolated from the blood of identical donors from which lung organoids are generated. The background is that influenza-specific T cells, which form part of the acquired immune defense, can provide a tool to fight viral infections when antiviral drugs are not sufficiently effective in immunocompromised or -suppressed individuals. T cells recognize and eliminate virus-infected lung cells, recruit and activate other immune cells, and help maintain organ integrity as well as terminate infection. In order to assess the safety and efficacy of this therapeutic approach, appropriate preclinical test systems are needed. This is where the project of Dr. Andy Römhild and Dr. Leila Amini from the Berlin Center for Advanced Therapies (BeCAT) and Prof. Andreas Hocke from the Department of Infectious Diseases, Pneumology and Intensive Care Medicine comes in. In the long term, the researchers want to establish a new platform suitable for preclinical testing of virus-specific T cell products on human organoids.

The three projects will be funded with a total of 537.000 Euros over a period of two years starting in January 2023.


Charité 3R Research Funding


Charité 3R

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