French scientists find new use for anti-rejection drug

Immunofluourescence picture of a neuron, with huntintgtin stained red, courtesy Institut Curie

French researchers have discovered that an anti-rejection drug could treat Huntington's disease, a hereditary neurological disorder of the central nervous system that causes progressive degeneration of cells in certain areas of the brain, slowly impairing a person's ability to walk, think, talk and reason.

In a collaboration, researchers at the Institut Curie, CNRS and Inserm have found that Huntington's disease may be treated using FK506, which is marketed for the prevention of graft rejection after transplant surgery. FK506 could block the toxicity of the protein huntingtin, which causes some neurons to die, leading to the onset of the disease.

As FK506 is already used therapeutically to prevent graft rejection, it may be a candidate for fast-track development as a treatment for Huntington's disease. Emmanuelle Deponge, a licensing officer of Institut Curie, said intellectual property based on the research is available for licence.

The symptoms of Huntington’s disease develop gradually over months or years. The age at which they first appear varies between about 30 and 50, though some people develop symptoms earlier on or later in life. The onset and the rate of progression of the disease tend to follow a pattern within each family.

Huntington's disease results from changes in the IT15 gene, which encodes a protein, huntingtin, whose function is incompletely elucidated. Normal huntingtin contains repeats of the amino acid glutamine, but mutant huntingtin contains more than 35 to 40 glutamines and induces the disease.

This abnormal expansion of glutamine results in structural changes, and the mutant huntingtin accumulates in neurons, causing them to malfunction and ultimately to die.

Raúl Pardo and Emilie Colin at the Institut Curie are studying the mechanisms that lead to neuron death in Huntington's disease, under the direction of Frédéric Saudou and Sandrine Humbert. They have now shown that calcineurin, a protein abundant in the brain, chemically alters mutant huntingtin, which becomes more toxic to neurons.

They have also discovered that by inhibiting calcineurin, FK506 "corrects" this chemical alteration in mutant huntingtin both in cultured neurons and in an animal model of the disease.  

“The drug FK506 is able to block the activity of calcineurin, having a direct effect on the huntingtin protein,” said Frédéric Saudou, group leader of the research team, in an interview. “Then the huntingtin gets less toxic.”