Geneva Watch Days: watchmakers more motivated than ever

Lausanne and French researchers have succeeded in counteracting the impairment of cognitive functions associated with trisomy 21 with hormone therapy. These results, published Thursday in the journal Science, were obtained during a pilot study in seven patients.

Down syndrome, or trisomy 21, affects one in 800 births and results in a variety of clinical manifestations, including cognitive decline. A progressive loss of smell is also common from the prepubertal period onwards, and males may have deficits in sexual maturation.

Three quarters of those affected develop dementia with increasing age. “It’s like early Alzheimer’s syndrome,” Nelly Pitteloud, a professor at the University of Lausanne and head of the Department of Endocrinology, Diabetology and Metabolism at the Center Hospitalier Universitaire Vaudois (CHUV), told Keystone-ATS – author of this study – French colleagues Ins.

Recent discoveries suggest that neurons expressing the hormone GnRH (gonadoliberin), known to regulate reproduction via the hypothalamus, are also active in other regions of the brain, particularly with a role in cognition. Based on this idea, a group of researchers from the Inserm in Lille (F), led by Vincent Prévot, studied the mechanism of regulation of GnRH in mouse models of trisomy 21.

The team was able to show that five microRNA strands involved in the production of this hormone and present on chromosome 21 were deregulated. This extra chromosome then leads to abnormalities in the neurons that secrete GnRH.

Restore GnRH production

“Then we were able to show that reactivation of a GnRH system made it possible to systematically restore cognitive and olfactory functions in mice with Down syndrome,” said Vincent Prévot during an online press conference.

These findings in mice were discussed with Nelly Pitteloud, whose group is an expert in the diagnosis and treatment of a rare disease, congenital GnRH deficiency, which is characterized by the absence of puberty. These patients are given pulsatile GnRH treatment, which is administered at regular intervals to replicate the natural rhythm of this hormone’s release.

The researchers therefore decided to test the effectiveness of such a treatment on Down syndrome mice. Result: After 15 days, they had regained their olfactory and cognitive functions.

Improved cognitive functions

The CHUV doctors have therefore moved on to the next phase, a pilot study on patients referred by Ariane Giacobino, Head of the Trisomy 21 Clinic at the University Hospitals of Geneva.

Seven men with trisomy 21, aged 20 to 50 years, received a dose of GnRH every two hours subcutaneously with an arm-mounted pump for six months. Cognitive and olfactory tests as well as MRI scans were performed before and after treatment.

In the end, cognitive performance increased in six of the seven patients: better three-dimensional representation, better understanding of instructions, improvement in reasoning, attention and episodic memory. On the other hand, the treatment had no effect on the sense of smell.

New brain mapping

These cognitive tests were confirmed by brain imaging at the CHUV, which showed a significant increase in functional connectivity. “We can see a new brain map approaching healthy subjects, it’s exciting,” noted Nelly Pitteloud.

The improvement is estimated at 10% to 30%. One of the participants even “exceeded the bar of the healthy subject”, noted the Lausanne professor, who, however, specifies that the study population was made up of subjects who were very much surrounded and stimulated by their relatives.

The authors want to be careful. These results need to be confirmed by a larger randomized study with a control group receiving a placebo. It starts this fall in Lausanne and Basel and includes around sixty patients, including women. It should last two years.

“In trisomy 21, pulsatile GnRH therapy is promising, especially since it is an existing treatment and there are no significant side effects,” concludes Nelly Pitteloud. “There is nothing better than a natural hormone that can be easily administered in physiological doses,” added Vincent Prévot.

A patent has been registered and a start-up is planned. If it ever comes to market, the treatment could take the form of a pump, similar to that used by diabetics. These results also offer research opportunities for other pathologies, particularly Alzheimer’s.

This article was published automatically. Source: ats

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