It is well known that Down syndrome (DS) is caused by alterations in chromosome 21, trisomy in the vast majority of cases. At the phenotypic level, it has multiple anatomical, physiological and neurofunctional manifestations, including intellectual disability. Due to its polygenic nature,¹ it has no cure, and standard therapeutic measures can only partially alleviate patients’ disabilities. Although there is still no specific treatment aimed at improving the capacity of people with DS, several years ago it was found that treatment with epigallocatechin gallate, a natural product present in some vegetables, improves some cognitive deficits in animal models of Down Syndrome and in preliminary clinical trials conducted in human patients with DS.¹ Epigallocatechin gallate is a potent inhibitor of an enzyme encoded by the DYRK1A gene, present on human chromosome 21. Trisomy of this chromosome results in elevated levels of the enzyme, which is considered responsible for at least some of the cognitive deficits associated with DS. The results of the first phase 2 clinical trial were published in 2016.² The most recent one was carried out by the PERSEUS group, which includes Hospital del Mar (Barcelona), Hospital Universitario Sant Joan (Reus), Hospital del Niño Jesús (Madrid), Instituto Hispalense de Pediatría (Seville), the University of Cantabria, Hospital Marqués de Valdecilla (Santander) and the Institut Jérôme Lejeune (Paris). The study, published in 2022, concluded that although the compound was well tolerated and had some beneficial effects on adult cognitive ability, its administration had no benefits in patients with DS.3

The disappointing results of the aforementioned trials should not make us lose hope of finding an effective treatment to alleviate, even partially, the disabilities produced by Down Syndrome. On the contrary, they should serve to maintain that hope, since there are groups of researchers eager to find a pharmacological treatment for the condition. Two recent studies should be mentioned in this regard, both of which used animal models of DS, specifically Ts65Dn mice or Dp(16)1Yey mice, which possess three copies of most of the genes orthologous² to the genes of human chromosome 21. Both types of mice have been obtained through genetic engineering techniques and their behavior reproduces many of the deficiencies associated with human DS.

The first study, published in 2022 and conducted by a team of researchers from 18 centers in France, Switzerland, Spain and Germany, studied the effects of treatment with gonadotropin-releasing hormone (GnRH).4 The primary function of this hormone, which is synthesized primarily in neurons of the hypothalamus and is secreted in a pulsatile manner, is related to reproduction. However, it is also synthesized in extra-hypothalamic areas, so it can participate in other brain processes.5 Based on these and other similar data, the study authors confirmed that the loss of olfactory and cognitive capacity of Ts65Dn mice is related to the decrease in the synthesis and secretion of GnRH, and that restoring the hormone levels using different methods improves the aforementioned disabilities. They also conducted a pilot study with seven adult men with DS, to whom they gave pulsatile GnRH therapy, also observing an improvement in their cognitive deficits.4

The second study is much more recent – it was published on 13 May this year – and presents important novel features.6 It was carried out by a team of 12 scientists from five French research centers, led by Nathalie Janel. Dp(16)1Yey mice were used and the compound tested was preimplantation factor (PIF), a peptide of embryonic origin whose primary function is to protect embryos against various insults, such as oxidative stress, during pregnancy. However, it also shows neuroprotective functions,7 so Janel’s group adopted this peptide as the object of their trials. The novelty of the research is that, taking into account that, in DS, the neurofunctional impairment begins during gestation, the peptide was administered to pregnant females from day 14 after intercourse3 until weaning of the offspring.

The treatment had no negative effects on the mothers or on survival of the young. With a sufficient number of animals for the results to be statistically significant, Janel’s group administered PIF to one set of pregnant females, while another set of animals received control treatment without PIF. To evaluate the effects of the treatment on the cognitive ability of the mice, several tests were carried out: communication ability (through the study of ultrasonic vocalization) 4; social behavior (estimated by the olfactory recognition of their nest after being separated from it); and spatial memory (assessed in a maze). The research included molecular studies, such as change in the expression of genes associated with apoptosis,5 as well as markers of neurogenesis and inflammation, and was completed with histological analysis of neurogenesis.

While the Dp(16)1Yey mice presented impairments in all the parameters analyzed — somewhat mimicking those present in patients with Down Syndrome — in all cases, the PIF treatment managed to improve those impairments, an improvement that was observed in the offspring from day 7 to adulthood.

The findings discussed, especially those of the studies with GnRH and PIF, spark a glimmer of hope for the future of patients with DS. Of course, these data — preclinical or even at the basic science level — are just the starting point of a long road, which will require more preclinical studies and, where appropriate, relevant clinical trials. This situation obviously means it is premature to say that the impairments caused by DS can be treated pharmacologically; it would not be acceptable from an ethical point of view to create false expectations, as if the solution were just around the corner. Nevertheless, we can look to the future with optimism, even hoping that, once DS is diagnosed in a fetus, the mother can undergo treatment that will improve her child’s quality of life. And, of course, it is hoped that, thanks to the progress of research and the necessary parallel moral rearmament, the number of abortions taking place after a prenatal diagnosis of DS will be reduced, or even eliminated.

Luis Franco

Member of the Spanish Royal Academy of Sciences

Member of the Bioethics Observatory

 

[1] A genetic disorder is said to be polygenic when it is caused by abnormalities in several genes.

[2] The Scientific and Technical Vocabulary of the Spanish Royal Academy of Exact, Physical and Natural Sciences defines orthology as: “Homology in which related biological entities, usually nucleic acid or protein sequences, come from different species that derive from a common ancestral species”.

[3] In mice, gestation lasts 20 days. The offspring are weaned when they are 21 days old, reach puberty at 40-50 days and, from 2 months old, can be considered adults.

[4] Mice and other rodents are able to emit ultrasounds, not perceptible by the human ear, which serve as a means of communication in circumstances of some risk, such as, for example, when the pups are separated from their mothers.

[5] Apoptosis, programmed cell death, is a process that organisms use to destroy damaged cells. In DS, uncontrolled apoptosis leads to loss of neurons.

REFERENCES

  1. De la Torre, R.; De Sola, S.; Pons, M.; Duchon, A.; de Lagran, M.M.; Farré, M.; Fitó, M.; Benejam, B.; Langohr, K.; Rodriguez, J.; et al. Epigallocatechin-3-Gallate, a DYRK1A Inhibitor, Rescues Cognitive Deficits in Down Syndrome Mouse Models and in Humans. Molecular Nutrition and Food Research 2014, 58, 278–288, doi:10.1002/mnfr.201300325.
  2. de la Torre, R.; de Sola, S.; Hernandez, G.; Farré, M.; Pujol, J.; Rodriguez, J.; Espadaler, J.M.; Langohr, K.; Cuenca-Royo, A.; Principe, A.; et al. Safety and Efficacy of Cognitive Training plus Epigallocatechin-3-Gallate in Young Adults with Down’s Syndrome (TESDAD): A Double-Blind, Randomised, Placebo-Controlled, Phase 2 Trial. The Lancet Neurology 2016, 15, 801–810, doi:10.1016/S1474-4422(16)30034-5.
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  4. Manfredi-Lozano, M.; Leysen, V.; Adamo, M.; Paiva, I.; Rovera, R.; Pignat, J.M.; Timzoura, F.E.; Candlish, M.; Eddarkaoui, S.; Malone, S.A.; et al. GnRH Replacement Rescues Cognition in Down Syndrome. Science 2022, 377, eabq4515, doi:10.1126/science.abq4515.
  5. Skrapits, K.; Sárvári, M.; Farkas, I.; Göcz, B.; Takács, S.; Rumpler, É.; Váczi, V.; Vastagh, C.; Rácz, G.; Matolcsy, A.; et al. The Cryptic Gonadotropin-Releasing Hormone Neuronal System of Human Basal Ganglia. eLife 2021, 10, e67714, doi:10.7554/eLife.67714.
  6. Moreau, M.; Dard, R.; Madani, A.; Kandiah, J.; Kassis, N.; Ziga, J.; Castiglione, H.; Day, S.; Bourgeois, T.; Matrot, B.; et al. Prenatal Treatment with Preimplantation Factor Improves Early Postnatal Neurogenesis and Cognitive Impairments in a Mouse Model of Down Syndrome. Cell and Molecular Life Sciences 2024, 81, 215, doi:10.1007/s00018-024-05245-9.
  7. Mueller, M.; Schoeberlein, A.; Zhou, J.; Joerger-Messerli, M.; Oppliger, B.; Reinhart, U.; Bordey, A.; Surbek, D.; Barnea, E.R.; Huang, Y.; et al. PreImplantation Factor Bolsters Neuroprotection via Modulating Protein Kinase A and Protein Kinase C Signaling. Cell Death and Differentiation 2015, 22, 2078–2086, doi:10.1038/cdd.2015.55.

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