Scientists develop the first human model for the rare, incurable Lee syndrome

Lee syndrome is the most dangerous mitochondrial disease in children. It is a condition that causes severe muscle weakness, movement impairments and intellectual disabilities.

Lee syndrome usually leads to death during the first years of life. There is no causal treatment currently available. One of the genes that develops a lot in patients is the SURF1 gene, which encodes a protein involved in the generation of energy in cells.

Animal models did not summarize the defects seen in patients carrying the mutations in SURF1. Therefore, scientists did not have the tool to begin to understand disease mechanisms and define potential targets for treatment. But they recently reported the first human model of this rare disease in the journal Nature Communications, published on March 26.

The Max Delbrueck Center for Molecular Medicine (MDC) has now developed the first human model for Lee syndrome caused by mutations of SURF1, in collaboration with the group of Professor Alessandro Brigioni in the Department of General Pediatrics at the University Hospital Düsseldorf, Germany, and the groups of Professor Markus Schwylk in the Department of Neurology at the Charité University in Berlin, Professor Nicholas Rajowski at the Berlin Institute for Medical Systems Biology (BIMSB).

To achieve this, the authors used cellular reprogramming technology, which enables the transformation of cells from the skin into stem cells capable of generating neurons. Then they used CRISPR / Cas9 molecular scissors to precisely remove the mutation from the patient’s cells and introduce the mutations into the control cells. Thus the authors were able to investigate the specific effect of SURF1 mutations in a controlled genetic background. They then generate neurons and brain organelles, which are three-dimensional in structure and reproduce the early development features of the human brain.

Using these models, the scientists discovered that the neural defects seen in the patients may be caused by the lack of energy that occurs at the level of neuronal precursors, the cells that generate neurons.

These energy deficiencies lead to insufficient branching of nerve cells, which leads to impaired brain function during development. Finally, the authors state that branching defects can be corrected by improving energy production for progenitor cells using SURF1 gene replacement therapy or with Bezafibrate, which is currently safe for clinical use in children.

These results are important because they provide for the first time a model for studying the neurological diseases of Lee’s syndrome caused by mutations of SURF1, as well as practical strategies for treating children with the rare disease with high medical needs.

Source: medicalxpress

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