A paper, published September 2 in the journal Science, describes work in mice to show the role GnRH plays in Down syndrome and a pilot study that marked the start of an attempt to translate that knowledge into a treatment for the condition. In the preclinical part of the study, the researchers saw a correlation between decreased hypothalamic and extrahypothalamic GnRH expression and the cognitive and olfactory deficits associated with Down syndrome.

Specifically, the symptoms appear to relate to an imbalance in a microRNA (miRNA)-gene network that is known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. The team showed five strands of miRNA that regulate the production of GnRH were dysfunctional, findings that they then confirmed at the genetic and cellular levels.

Using epigenetic, cellular, chemogenetic, and pharmacological interventions to restore physiological GnRH levels abolished olfactory and cognitive deficits in mice, leading to the development of a pulsatile GnRH therapy. In mice, the therapy restored olfactory and cognitive function after 15 days.

In a mouse model of the condition, the researchers found that the progressive nonreproductive neurological symptoms seen in Down syndrome closely parallel a post-pubertal decrease in GnRH expression. The pilot study built on work in mice that shed light on the role GnRH may play in Down syndrome.

To test the pulsatile GnRH therapy in humans, the researchers enrolled seven men between the ages of 20 to 50 with Down syndrome. Researchers administered GnRH to the men every two hours for six months via a pump placed on the arm. Cognitive performance improved in six of the seven participants, who had better three-dimensional representation, understanding of instructions, reasoning, attention, and episodic memory after the treatment.

While most participants had improved cognitive function, coupled to a significant increase in functional connectivity, the treatment had no effect on the ability of participants to smell. Decreased ability to smell is present in adults with Down syndrome, many of whom are known to have brain pathology analogous to that seen in Alzheimer's disease. Currently, no viable treatment exists for the cognitive and olfactory deficits seen in Down syndrome patients.

"Maintaining the GnRH system appears to play a key role in brain maturation and cognitive functions," Vincent Prévot, research director at Inserm and co-author of the paper, said in a statement.

Nelly Pitteloud, professor at the University of Lausanne and co-author of the study, added that "pulsatile GnRH therapy is looking promising, especially as it is an existing treatment with no significant side effects."

The researchers contend that their findings have paved the way for future clinical trials -- with the inclusion of women -- to not only confirm the efficacy of the GnRH therapy in patients with Down syndrome, but also for other neurodegenerative conditions such as Alzheimer's disease.

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