Gonadotropin-releasing hormone therapy in trisomy 21

Treatment with gonadotropin-releasing hormone (GnRH) appeared to normalize neurologic and cognitive deficits in a mouse model of Down syndrome and to have positive effects in a small, open-label trial, a paper in Science reported.

The results were considered promising enough that the authors are now recruiting 60 patients for a randomized clinical trial.

“The maintenance of the GnRH system appears to play a developmental role in brain maturation and higher functions,” the study authors concluded. “Pulsatile GnRH therapy holds promise to improve cognitive deficits in DS, paving the way for future clinical trials.”

Study Details

The study grew out of an observation that some of the non-cognitive symptoms of Down syndrome are like those seen in patients with a deficiency of GnRH, said senior author Vincent Prevot, PhD, senior research director of the National Institute of Health and Medical Research (Inserm) in Lille, France, where he leads the development and plasticity of the neuroendocrine brain study group at the Lille & Cognition Research Center.

In particular, he said, the impaired secretion of GnRH seen in Kallmann syndrome results in subfertility, a trait also seen in Down syndrome. In addition, children with Kallmann lack olfaction from birth, while children with Down syndrome have the sense of smell during childhood, but lose it during adolescence.

To test their hypothesis that Down syndrome may be caused in part by low levels of GnRH, the French team conducted over a dozen experiments with the Ts65Dn mouse model of Down syndrome.

“We saw that the pups were initially able to smell correctly,” Dr. Prevot said. “They could find the nipples of the mother. But they were losing the sense of smell just before puberty, like the type of progression that we see in humans with DS.”

After puberty, they observed loss of GnRH neurons and fibers in the hypothalamus and beyond. The decreased GnRH expression, in turn, occurred at the same time as an “imbalance” emerged in microRNAs and other regulatory factors that act as a kind of “switch” controlling GnRH expression and neuron maturation.

“This altered expression of microRNAs and transcription factors in the hypothalamus appeared to result in the altered expression of a number of target genes, as well as in the altered activity of hippocampal neurons,” the study stated.

To try to correct the deficits, Dr. Prevot and colleagues over-expressed one of the key microRNAs involved in GnRH development in the hypothalamus. The result was a normalization of neuronal activity in the hypothalamus, olfaction, and cognition in the Down syndrome mice, as measured by the novel object recognition test. Neurons expressing GnRH, they found, projected outside of the hypothalamus and into cortical regions of the brain.

To be sure that the changes were because of restoration of GnRH, the researchers used three other methods—cell therapy, chemogenetics, and drugs—to raise GnRH levels to normal. To mimic the way that GnRH is released by the body in pulses, they used a miniature pump. The result was that the olfactory and cognitive deficits in the mice were abolished.

Based on the results in mice, Dr. Prevot and colleagues conducted an open-label pilot study in seven adult males with Down syndrome. Again, seeking to replicate the normal physiologic release of GnRH in pulses, they used a programmable pump that delivered a pulse of the hormone subcutaneously once every two hours for six months. Although it had no effect on olfaction, each of the seven patients showed gains on the Montreal Cognitive Assessment (MoCA) test.

“We had only seven patients in an open-label design,” Dr. Prevot said, “so the results are interesting, but we need to take them with a lot of caution. We need to validate them with a bigger group. We will launch a randomized, double-blind, placebo-controlled trial on 60 patients this fall, with men and women.”

Whether the results are permanent or temporary, he said, remains to be determined. And while teenagers as young as 14 or 15 could potentially receive the treatment, he said, children younger than that would be ineligible, as GnRH affects sexual maturation.

Expert Commentary

Four of five neuroscientists active in the study of Down syndrome and contacted by Neurology Today said that the study had such serious methodological flaws that a clinical trial is not yet appropriate, however.

“Effective translation requires that preclinical work is both robust and generalizable,” said Frances Wiseman, PhD, program leader for animal models at the UK Dementia Research Institute at University College London. “I have concerns that should be addressed prior to expanding this work to a full, multicenter clinical trial as proposed in the paper.”

Because the preclinical experiments involved only one mouse model of Down syndrome and measured their cognition using primarily a single behavioral test, the experiments need to be repeated with a second mouse model and more tests of learning and memory, several independent experts said. And they were particularly critical of the open-label test of the treatment in seven male adults with DS, given the strong placebo effect seen in prior studies of DS treatments.

https://journals.lww.com/neurotodayonline/Fulltext/2022/10060/Can_Gonadotropic_Replacement_Improve_Cognition_in.6.aspx

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.

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.