Trisomy 21: an effective therapy for cognitive decline

Down syndrome, or trisomy 21, occurs in about one in 800 newborns in France. Symptoms include cognitive decline: as they age, 77% of people with trisomy 21 experience symptoms similar to those of Alzheimer’s disease, a progressive loss of smell (typical of neurodegenerative diseases), and a lack of puberty in men. . “At age 65, 75% of people with trisomy 21 have dementia. And those who have already died at the age of 40 (people with this syndrome have a reduced life expectancy) all have brain scans that are characteristic of Down’s disease. Alzheimer’s disease,” explains Vincent Prevost. , neuroscience researcher at Inserm. So far, there has been no way to counter these symptoms. But the team of Vincent Prevost from the Laboratory of Neurology and Cognition of Lille (Inserm/University of Lille/CHU Lille) and the Hospital Center of the University of Vaud (CHUV, Lausanne) has just demonstrated the effectiveness of hormonal treatments that can improve people’s cognitive functions. with trisomy 21. Unpublished work published in the journal Science.

Confirmed Role of the GnRH Hormone

This potential future treatment is based on the hormone GnRH (Gonadotropin-releasing hormone), which is known to regulate reproduction through the hypothalamus. The latter will also play a role in other areas of the brain, in particular in the cognition system. By studying the mechanism of GnRH regulation in mice, the Inserm laboratory team demonstrated that on chromosome 21, five microRNA strands that control the production of this hormone are dysregulated. They are responsible for the control of GnRH expression. However, the start of expression is altered in trisomic mice: this extra chromosome then leads to abnormalities in hormone-secreting neurons. On the other hand, by administering GnRH treatment to mice with Down syndrome, the team demonstrated recovery of cognitive and olfactory functions in mice.

Building on these results in rodents, the Inserm team continued to work with Nellie Pittelode, Professor at the Faculty of Biology and Medicine at the University of Lausanne and Head of the Department of Endocrinology, Diabetology and Metabolism at CHUV. A doctor who specializes in congenital GnRH deficiency, a rare disorder characterized by the absence of spontaneous puberty. These patients are given GnRH pulsatile therapy to replicate the natural pulsatile rhythm of GnRH secretion to induce puberty. This time, the treatment was in patients with trisomy 21. A small group of seven men, aged 20 to 50, received an implantable pump on their arm that delivered a dose of hormones every two hours. This medical device called a “capsule” is already being used to deliver insulin to people with diabetes. “It is not possible to administer this drug orally because GnRH is deactivated too quickly when taken orally,” says Professor Pittelowe.

Daily and visible results on medical imaging

From a clinical point of view, 6 out of 7 patients had improved cognitive functions: better three-dimensional representation, better understanding of instructions, improved reasoning, attention, and episodic memory. “We saw an improvement in attention and understanding of instructions. Brain imaging data also showed the restoration of neural connections using functional MRI, a study conducted at rest with eyes open, in particular between visual areas and sensorimotor areas,” explains Professor Nelly Pittelow. In particular, participants felt more at ease in the workshop where they worked and seemed more confident in everyday life, such as on the bus, according to peers. None of the seven participants had any side effects.

Functional MRI before treatment (left) and after treatment (right) showing restoration of neural connections between different brain regions. Photo: Nelly Pittelope / CHUV Lausanne.

“It is still unclear exactly how GnRH is secreted in patients,” explain the study authors, who emphasize the need for further work. “We need a larger study with more than seven patients that includes women as well as a control group (a group that is given a placebo to ensure the effect of the treatment, editor’s note). The randomized trial will start this fall in Basel. and Lausanne. It will include from 50 to 60 people. If after six months of treatment the effect does not continue, we will switch to a longer treatment.” One way would also be to start treatment as soon as possible to prevent progressive cognitive loss. CHUV in Lausanne has already signed a contract with the French laboratory Ferring, which sells the hormone (6 months of treatment currently costs 15,000 euros). If the discovery is patented, the commercialization of the treatment will have to wait a bit. Initially, a randomized trial should last two to three years.

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