Restoring neuronal transmission at birth might prevent the onset of Huntington’s disease in adulthood, according to a recent study. A promising avenue for overcoming this incurable disease which affects 18,000 French people?
Balance and cognitive disorders, sudden, unpredictable and involuntary movements of the four limbs… The symptoms of Huntington’s disease generally appear between the ages of 30 and 50 and then gradually worsen. The manager ? The gene coding for a protein called “huntingtin”, essential for the proper functioning of neurons. This rare pathology being triggered late, the consequences of this mutation on pre- and postnatal neurodevelopment had, until then, been little studied… This era is now over. On September 22, 2022, researchers from Inserm (National Institute for Health and Medical Research)* highlighted the impact of the disease on the quality of nerve transmission in certain neurons very soon following birth, with anatomical and behavioral effects. This unprecedented discovery, published in the scientific journal Scienceopens new avenues of research on the therapeutic care of the 18,000 French people affected by this incurable disease.
Alteration of nerve transmission
It was Sandrine Humbert, Inserm research director, and her team who, in 2020, revealed the impact of cerebral anomalies in the brains of human embryos carrying the mutation responsible for this rare genetic pathology. “Several functions regulated by neuronal activity appeared to be impacted, suggesting an alteration in nerve transmission,” she explains. Faced with this observation, she became interested in the establishment of neural circuits and in cognitive and sensory-motor behaviors in model mice of Huntington’s disease. The researchers then observed different alterations: “the pyramidal neurons of their cerebral cortex showed morphological and synaptic transmission defects, associated with behavioral alterations”. But, following 21 days of life, they found a physiology and a morphology “apparently similar to those of healthy mice”. “However, these compensations would only work for a time since from four to five weeks, the mice develop certain signs of the disease”, emphasizes the researcher.
CX516, neuronal activity booster
The scientists then hypothesized that a restoration of the transient defects observed during the first week of life might influence the onset of the disease in adulthood. To verify this, they used a therapeutic molecule from the ampakine class (known to increase the capacity for attention and alertness but also to facilitate learning and memory), CX516, which aims to facilitate nerve transmission. Bingo! This neonatal treatment made it possible to restore the neuronal activity and the cognitive and sensory-motor capacities of the mouse pups and, above all, prevented them from developing the characteristic signs of the disease in adulthood.
Further research on brain development
“While these results obtained in animals plead in favor of an early treatment of people affected by Huntington’s disease, they also invite to deepen the understanding of brain development in the context of this pathology”, urges Inserm. They also call, according to him, to discover the links between the anomalies caused by the disease and the compensatory mechanisms put in place by the organism before the appearance of the symptoms.
Another promising treatment?
Inserm is not at its first attempt to fight Huntington’s disease. In April 2021, researchers had tested the therapeutic molecule ML348 on mice to “protect the brain from neuronal death”, obtaining “promising” results such as the reduction of behavioral, motor and psychic disorders (full article in link below). Next step ? Preclinical trials intended to “evaluate on cellular and animal models the behavior of the molecule in the body, its safety of use or even to identify the effective doses”. As a reminder, if the treatments currently offered are symptomatic and relieve certain disorders, they do not make it possible to modify the course of the disease. Is that regarding to change soon?
* and the University of Grenoble Alpes, within the Grenoble Institute of Neurosciences
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