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Ongoing research

Therapy for rare diseases….. a dot on the horizon

Rare disorders collectively account for a large disease burden in society. However, because of the small number of patients for each individual rare disorder, developing drug-based therapies has been commercially unattractive for pharmaceutical companies. New approaches for cost-effective identification of drugs for rare disorders are urgently needed.

The groups of researchers Kees Albers, Nael Nadif Kasri and clinician Bert de Vries from the department of Human Genetics, Radboud university medical center (Nijmegen, the Netherlands) have recently started a new project to develop such a method for Koolen-de Vries syndrome. KdVs patients have intellectual disability, hypotonia, epilepsy and characteristic facial features. Mutations in the causative KANSL1 gene, encoding an epigenetic regulator, cause widespread dysregulation of gene expression during neurodevelopment. However, it is not known which specific molecular mechanisms are disrupted and which drugs can specifically target the affected biological pathways.

The new approach is based on studying ‘brains in a dish’. We start by taking a few skin or blood cells from a patient with Koolen-de Vries syndrome. These skin cells can be transformed into stem cells. Stem cells have the unique property that they can be differentiated into any cell type in our body. We differentiate the stem cells into neurons in a petri-dish. After a few weeks, the neurons start to communicate with each other using electrical signals. We can measure these signals with tiny electrodes to study how neuronal communication is affected in patients.

To find new drugs, we first measure the activity of each gene in these neurons of patients. We then compare the gene activity profile of a patient to that of a group of unaffected individuals. As we measure thousands of genes, this comparison results in a gene activity fingerprint that is unique to the patient and the disorder. With this fingerprint we can now interrogate a new publicly accessible database that records how gene activity is changed if a certain drug (molecule) is administered to a certain type of cell. There are already 27,927 drugs in the database. Specifically, we look for a drug that changes the activity of genes in a such a way that the expression profile of the patients is predicted to become more like that of an unaffected person.

With this approach, we hope we can use the computer to narrow down the list of 27,927 possible drugs to a much smaller number, which we can then experimentally validate on the patient-derived brain cells in the dish. This may substantially reduce the time and cost needed to identify candidate therapeutics for Koolen-de Vries syndrome and other rare genetic disorders.