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GnRH replacement shown to improve cognitive deficits in people with Down syndrome

A new study shows GnRH therapy may be an effective treatment for improving cognitive deficits associated with Down syndrome. (Image: Down syndrome karyotype, Wikimedia/Josef Reischig)

Down syndrome is a genetic condition where a child inherits an extra chromosome from their parents, resulting in the acquisition of three (3) copies of chromosome 21. This condition is commonly referred to as trisomy 21.

The onset of puberty in people with Down syndrome is often accompanied by decreased cognitive and olfactory function, including impaired odor detection. Currently, no effective therapy is available for treating these abnormalities.

A recently published study has demonstrated that interventions that increase gonadotropin-releasing hormone (GnRH) in adult men with Down syndrome resulted in improvements in cognitive function. The research team out of the University of Lille, and in collaboration with the French National Institute of Health and Medical Research, first conducted an animal study using post-pubescent trisomic mice and found that the decreases in GnRH levels occurred alongside the dysregulation of certain microRNAs— a biological molecule involved in gene regulation— around chromosome 21. 

The researchers chose to alter the levels of miR-200b, a critical microRNA involved in GnRH gene expression. MiR-200b is an important microRNA that is frequently downregulated in people with Down syndrome, as well as in people with other neurocognitive disorders, such as Alzheimer’s disease. 

The animal study demonstrated that overexpressing miRNA-200b in the mice led to increases in hypothalamic GnRH levels, which resulted in improvements in Down syndrome-related olfactory and cognitive deficits.

One of the authors of the paper, Vincent Prevot, PhD., explained the decision to follow up with a small clinical trial. He told Scientific American, “These results were so convincing that our clinical colleague said, ‘We have to try this in Down syndrome patients.’”

Prevot added, “Six out of seven patients improved their cognitive tests by 20 to 30 percent. Even more amazing, we saw that functional connectivity was tremendously increased in all seven in cortical areas involved in speech and 3-D orientation.”

These findings have led to a larger randomized controlled clinical trial involving sixty-four (64) men and women with Down syndrome, which is intended to begin at the end of this year.

The study was published in Science on September 2nd, 2022.

Abstract. At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction—gonadotropin-releasing hormone (GnRH)—and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.

Manfredi-Lozano M, Leysen V, Adamo M, Paiva I, Rovera R, Pignat JM, Timzoura FE, Candlish M, Eddarkaoui S, Malone SA, Silva MSB, Trova S, Imbernon M, Decoster L, Cotellessa L, Tena-Sempere M, Claret M, Paoloni-Giacobino A, Plassard D, Paccou E, Vionnet N, Acierno J, Maceski AM, Lutti A, Pfrieger F, Rasika S, Santoni F, Boehm U, Ciofi P, Buée L, Haddjeri N, Boutillier AL, Kuhle J, Messina A, Draganski B, Giacobini P, Pitteloud N, Prevot V. GnRH replacement rescues cognition in Down syndrome. Science. 2022 Sep 2;377(6610):eabq4515. doi: 10.1126/science.abq4515. Epub 2022 Sep 2. PMID: 36048943.

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