Scientists from the University of Würzburg have discovered a promising approach to treat a genetically caused nervous disease. Instead of resorting to gene therapy, the scientists have targeted phagocytes they identified as promoters of the disease.
Charcot-Marie-Tooth (CMT) disease is a group of inherited disorders of the peripheral nervous system characterised by loss of nerve fibres, muscle tissue and impaired touch sensation. Early symptoms include paralysis and loss of muscle tissue in the feet and legs expanding to the hands and lower arms as the disease progresses. In severe cases, sufferers need a wheelchair; and there is no efficient therapy available at present.
Publication in the journal Brain
This could change in the foreseeable future: Scientists at the Department of Neurology of the University Hospital of Würzburg have found a target for therapy that was successfully applied in animal tests. The team of Professor Rudolf Martini, head of Experimental Developmental Neurobiology at the Department of Neurology has now published these findings in the renowned journal Brain.
"Normally, one would expect a gene therapy approach when treating an inherited disease," Martini explains. But he and his team took a different direction: They blocked a receptor on the surface of special cells of the immune system, the so-called macrophages.
A semiochemical gives the cue to attack
In previous studies conducted over several years, the scientists had used model mice to demonstrate that these macrophages cause the genetically predisposed nerve damage to occur in the first place. "You could say that they act as a promoter of the disease," Martini further. A special semiochemical, the cytokine colony-stimulating factor (CSF) -1, signals the macrophages to attack the nerve fibres.
"Astonishingly, CSF-1 is not expressed by the mutated Schwann cells, but by hitherto neglected nerve fibroblasts," Martini says. Schwann cells form the myelin sheaths in the peripheral nervous system which act as a kind of insulation of the myelinated nerve fibres. Moreover, they are essential for the survival of the nerve fibres and thus for keeping the nerves functional.
Even though around 80 disease genes have been identified for CMT neuropathies so far, the three most common forms of this disorder are caused by mutations of myelin associated genes of the Schwann cells. How the fibroblasts are informed about the defective Schwann cells is still unknown, but the scientists hope to decipher the mechanism during further studies.
Visible successes without side effects
In the study, the scientists fed a synthetic CSF-1 receptor inhibitor to mice suffering from CMT. As a result, the symptoms of two different forms of CMT were alleviated significantly and without side effects. The muscular strength experiments were particularly impressive and relevant for patients: "While untreated model mice lost up to 25 percent of their muscular strength due to the disease, the treated mutants cannot be distinguished from their healthy counterparts in terms of muscular strength," Martini says.
Hopes for a quick transfer to clinical practice
The scientists now believe that this approach is also highly significant for the treatment of humans. "Similar inhibitors are already being used in clinical studies to treat rheumatoid arthritis and different tumours," Martini explains. Protracted approval procedures to use the inhibitor on humans are thus already under way.
Dr. Brian West is one of the co-authors of the study besides the members of Martini's team. He is the research director of the Californian company Plexxikon which developed the inhibitor. The study has already drawn much attention, for example, in the form of a scientific comment by Professor Steven S. Scherer (Philadelphia), an international expert in CMT. In addition to Deutsche Forschungsgemeinschaft, the project received considerable funding from Charcot-Marie-Tooth Association in the US, which recently appointed Professor Rudolf Martini to its scientific advisory board.
According to Martini, the successful research project demonstrates that after exploring all other possibilities animal experiments are crucial to finding new approaches to treat and ultimately heal so far incurable human diseases.
Targeting the colony stimulating factor 1 receptor alleviates two forms of Charcot–Marie–Tooth disease in mice. Dennis Klein, Ágnes Patzkó , David Schreiber, Anemoon van Hauwermeiren, Michaela Baier, Janos Groh, Brian L. West and Rudolf Martini. BRAIN, published online August 21, 2015. doi:10.1093/brain/awv240
Prof. Dr. Rudolf Martini, Phone: +49 931 201-23268, firstname.lastname@example.org
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