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There are around 8,000 known rare diseases, and new ones are discovered every year. So, despite the rarity of the individual diseases, the total number of people affected is high: an estimated 5 percent of the world’s population. The EU, however, currently defines a disease as rare if fewer than 5 in 10,000 people have it. It often takes many years and many doctors to get a correct diagnosis. About 40 percent of patients are initially misdiagnosed, and many more never learn what is actually wrong with them. This is where the Case Analysis and Decision Support (CADS) platform can help. The joint project of the BIH and Charité provides patients at Berlin’s university medical center who have yet to receive a confirmed diagnosis with the ability to access in-depth clinical and molecular analysis.

The small number of affected individuals and their trans-regional geographic distribution also makes it difficult for researchers to conduct meaningful studies and develop effective therapies. But given that 80 percent of rare diseases are caused by abnormalities in a person’s genome, one cause for hope is gene- and cell-based therapies.

Gene- and cell-based therapies: young, flexible, and a focus area at the BIH

In the 30 years since the world’s first gene therapy took place in September 1990, researchers have developed a variety of new gene therapy techniques – not least the CRISPR-Cas gene-editing tool, which can be used to make precise, targeted changes to the genome and for whose discovery Emmanuelle Charpentier and Jennifer Doudna were awarded the 2020 Nobel Prize in Chemistry. Researchers at the BIH as well as BIH-funded companies are taking advantage of this modular principle to develop novel therapies for rare diseases.

Sarah Hedtrich is the Johanna Quandt Professor for Translational Human Organ Models at the BIH and is particularly interested in inflammatory and genetic diseases of the human skin and lung, such as ichthyosis. This family of rare skin disorders is caused by a single mutation in the gene for an enzyme that enables cross-linking of the cells in the upper layer of the skin. The result is an excessive keratinization of the skin, which prevents the formation of an intact skin barrier against pathogens. Hedtrich wants to develop a gene therapy to replace the faulty gene with a working copy. “We have already identified the gene and can correct the flaw using the CRISPR-Cas gene-editing tool. The only problem is how to get CRISPR-Cas into the diseased skin cells ?” is how Hedtrich describes the biggest challenge. One possibility is to encapsulate the gene-editing machinery and the corrected gene in lipid nanoparticles, which are also a key component of the Covid-19 mRNA vaccine, and deliver them to the skin cells via a cream and physical methods that temporarily weaken the barrier function.

Equally challenging is the act of delivering gene therapies to the site of disease in neuronal disorders. EpiBlok Therapeutics GmbH, founded by scientists from Charité and the Medical University of Innsbruck, is developing a gene therapy for focal epilepsy, in which there is often a supply shortage of the neuropeptide dynorphin. The scientists introduced the dynorphin gene into the affected neurons using a gene vector. The neurons then began producing and storing the dynorphin peptide. Prof. Christoph Schwarzer, a neuropharmacologist at the Medical University of Innsbruck and a co-founder of EpiBlok, explains what’s special about the therapy: “This is ‘drug on demand’ therapy. The neurons only release the stored peptide when it is needed, i.e., when the neurons are over-excited, like at the beginning of an epileptic seizure. Dynorphin calms the neurons, and the storm passes.” The scientists have already shown that this gene therapy is safe in mice, where it reliably suppresses epileptic seizures for several months after only one application. Charité BIH Innovation, the joint technology transfer office of Charité and the BIH, provided support in setting up the company and assistance in navigating the patent process. EpiBlok will soon make the leap to the clinic.

First clinical studies

MyoPax GmbH has already entered the clinical arena. Nature Medicine counts their clinical trial bASKet among the top eleven trials that will shape medicine in 2023. MyoPax has been part of SPARK-BIH, a support program of Charité BIH Innovation, since 2016. The team’s mission is to treat the root causes of muscle diseases, such as genetic muscle wasting disorders, and alleviate the symptoms of patients. The start-up was founded by physician Dr. Verena Schöwel-Wolf and neurologist Prof. Simone Spuler, who leads the Muscle Research Unit and the Outpatient Clinic for Muscle Disorders at the Experimental and Clinical Research Center, a joint institution of Charité and the Max Delbrück Center on Campus Berlin Buch.

Muscle stem cells are the only cells that can regenerate muscles. In patients who have a genetic muscular dystrophy these stem cells carry mutations, but MyoPax has used CRISPR-Cas and other tools to develop a method that corrects these mutations. The “repaired” muscle stem cells enable muscle to be rebuilt, which had so far been inconceivable in these muscular dystrophies. The bASKet trial will now test the safety of the therapy and plans to have the first data available in July 2023.

Translational center for gene and cell therapy

Myopax, Epiblok, and Sarah Hedtrich’s lab provide an exemplary glimpse into the possibilities that gene- and cell-based therapies offer in terms of creating the medicine of the future. Although gene therapy has been around for only about 30 years, it has already had some success in treating rare diseases. In April 2022, the State of Berlin, the pharma group Bayer, and Charité signed a memorandum to establish a translational center for gene and cell therapy. The BIH will be a central partner in the project. The center will exploit the potential of gene therapy and also expedite the transfer of research discoveries to patient care in line with the BIH’s mission.

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Katharina Kalhoff: +49 1515 7579574

Ole Kamm: +49 1522 5610126

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