Some 300 million people around the world suffer from rare diseases, which affect fewer than one in 3,000 people. Only some 6,000 of these diseases have been identified – and very few of them are curable. “Most rare diseases are caused by a defect in a single gene, targeted gene therapy can offer a chance for a cure,” says Dr. Ralf Kühn, head of the Genome Engineering and Disease Models Lab. It was Kühn who spearheaded the Max Delbrück Center’s participation in the doctoral network “Gene Therapy of Rare Diseases” (), which is part of the European Union’s Marie Skłodowska-Curie Actions (MSCA) program. He will supervise one of the ten funded young scientists.
Improving genome editing
The idea behind the EU project, which is funded to the tune of nearly €2.8 million, is to train promising young scientists in the development of gene therapies for rare diseases. The work of the PhD students should contribute in particular to the more precise delivery of genome editing tools into the target cells, as well as to improving the efficiency of gene editing and the safety of gene therapies.
The students, each of whom is based at one of the partner institutions, will complete two-month research stays with two other network partners – including one of the participating companies in the pharmaceutical/biotech industry. They will receive specialized training in a variety of relevant areas, including gene therapy technologies and molecular biology. Once they have completed the program, the young scientists should be able to translate their knowledge into therapeutically useful products. They are therefore also trained in entrepreneurial and legal issues, as well as in industrial project management. The program also covers important social and communication skills.
The GetRadi network is coordinated by Prof. Cord Brakebusch from the University of Copenhagen. A total of 14 institutions are involved, including three partners from industry. As one of the seven EU-funded partners, the Max Delbrück Center is receiving €260,500 for its participation. The , after which the selection process begins.
Disabling the cause of the disease
“We want to get started in mid-March 2023,” says Ralf Kühn. His GetRadi project is being run in cooperation with Prof. Markus Schülke from Charité – Universitätsmedizin Berlin, who has access to cells donated by a patient suffering from SYNGAP1 syndrome. This rare disease interferes with neuronal communication in the brain and thus disrupts, among other things, the motor and mental development of the affected child. “We will work on a gene therapy that disables the triggering gene,” reports Ralf Kühn.
Charité researchers have already obtained induced pluripotent stem cells from the mutated cells. The next step is to differentiate these into neuronal cells, following which an advanced CRISPR/Cas9 technique known as “base editing” will be used. Here, instead of full double-strand breaks being made, a single DNA base is exchanged as if with tweezers. The base editor, a fusion protein derived from the Cas9 “gene scissors,” specifically targets the mutated site in the DNA of the neurons in order to release the inhibition of protein production at the synapses. If the use of the base editor works as Kühn hopes, this gene therapy may offer a cure for a number of rare diseases.
Text: Wiebke Peters