Trisomy 21: A hormone opens up new avenues of treatment

People with trisomy 21 have very debilitating cognitive impairments. A pilot study whose results were published in the journal Science reveals the important role played by a hormone, GnRH, in these cognition problems. Vincent Prévot, neuroendocrinologist at Inserm, and Nelly Pitteloud, endocrinologist at the University of Lausanne, supervised this research, which could open up new therapeutic avenues. 

The Conversation: What is GnRH, the hormone that is the focus of your research?

Vincent Prevot: La gonadotropin releasing hormone, or GnRH, is the key reproductive hormone in all mammals, including humans. But its role does not end there.

It is a neurohormone, in other words a hormone which is secreted by certain nerve cells, the GnRH neurons. Unlike other neurons, these do not originate in the brain, but in the nasal cavity. They then migrate to the cerebral regions during the formation of the embryo. In humans, there are about 10, which is very few (it is estimated that the human brain has around one hundred billion neurons, editor’s note).

During development, GnRH neurons colonize the brain. Some stop at the level of the olfactory bulb, others migrate to certain regions of the cortex. About 2000 migrate into the hypothalamus.

Although few in number and scattered throughout the brain, GnRH neurons work in a coordinated fashion to secrete GnRH 'pulses'. These hormone peaks will be perceived by the pituitary as so many activating signals. In response, this gland will secrete other hormones, called gonadotropins, such as LH (Luteinizing Hormone, luteinizing hormone), which will act on the gonads (ovaries and testicles), promoting their growth and the production of gametes.

Beyond this central role in sexual functions, a link has also been established between GnRH neurons and olfaction. Indeed, in some people, the migration of GnRH neurons does not occur. We then observe not only an absence of puberty, but also anosmia, in other words an inability to perceive odors.

Beyond these two already known functions, for the first time, our work revealed the importance of GnRH in another area: cognition.

By giving GnRH to people with Down syndrome in a small "open label" pilot clinical trial (participants and clinical team members know they are getting the drug, no placebo being administered), we have indeed seen an improvement in their cognitive abilities. These results confirm what we had observed in an animal model of this condition, namely in mice.

TC: Why did you decide to take an interest in this hormone in the context of trisomy 21?

PV: We knew that in trisomy 21, the clinical characteristics of the disease, that is to say its manifestation, is exacerbated at the time of puberty. During their early childhood, patients with Down syndrome are able to perceive odors. However, they lose this ability quite quickly at puberty.

In the same way, if before puberty the learning abilities of children with Down syndrome are roughly equivalent to those of other children, their cognitive disorders worsen during this period of life, or just after.

A second reason made us look into trisomy 21: we knew that the GnRH promoter (the part of the DNA that controls its level of expression) is dependent on various microRNAs which are located on the chromosome 21, present in triplicate in this condition. We have also previously shown that several of these microRNAs played a fundamental role in the control of the GnRH promoter after birth.

If this “switch” no longer works properly, individuals will have GnRH deficiencies. This is perhaps what happens in patients with Down syndrome: the fact that the genes coding for these control micro-RNAs are present in 21 copies could disturb the GnRH neurons.

To verify these hypotheses, we started by studying the effects of GnRH in a mouse model with Down syndrome that mimics the effects of Down syndrome in humans. These rodents notably present problems of olfaction and diminished cognition in adulthood.

We administered GnRH to these model mice, at doses and under conditions (pulse) close to what occurs in wild (healthy) mice. Result: the simple fact of restoring a normal GnRH production rate to these animals resulted in an improvement in their olfactory and cognitive performance. This experience was the key to moving into the clinic, in other words in humans.

TC: This transition happened very quickly. Is it because GnRH was already used as a treatment for other indications?

Nelly Pitteloud: Indeed. GnRH is commonly administered by reproductive endocrinologists to restore fertility in patients who are congenitally deficient in this hormone. These are treatments on which we have a lot of experience: we know that they are well tolerated, have few adverse effects, do not pose any toxicity problems, etc.

Given these elements, we received the green light from the Ethics Commission in less than a year. After this authorization, we started recruiting patients. We immediately opened the study to men and women, but we did not have any patient applications meeting the inclusion criteria (in particular because the respondents had to not be on hormonal treatment). Our work therefore focused only on men aged 20 to 50 (seven in total).

The idea was to administer GnRH according to methods that mimic what was happening in individuals without Down's syndrome, then to measure any changes using a cognitive test (the MoCA test, Montreal Cognitive Assessment, chosen because it is short and adapted to people with intellectual and attention deficit) and functional magnetic resonance imaging (fMRI) examinations carried out before and after a 6-month treatment.

Why fMRI? Because we know that in the population without Down syndrome, there are connections, at rest, between the visual areas located at the back of the brain and the sensory-motor cortex, which is in a more anterior position. But in patients with trisomy 21, these connections are altered: some are minimal, others are too important.

Concretely, the participants were equipped with a pod (reservoir comprising a small cannula which passes under the skin) similar to that used to administer insulin to diabetics, but containing GnRH. The administration of the neurohormone is done via a "manager", a sort of computer which will send the order to inject the required quantity of GnRH between two-hour breaks (unlike pods diabetics, who diffuse insulin continuously). After six months of treatment, their cognitive performance was tested again, a new MRI was performed, and the data compared with that obtained before treatment.

TC: What did your results show?

NP: Above all, that the treatment had been well tolerated, with no adverse effects.

After six months, we saw improvements in the results obtained on the second cognitive test. However, we received these initial data with caution, because our study does not include a “randomized” control arm.

It should be noted that clinical studies may be subject to bias. One can imagine, for example, that the people who take care of the patients and want the treatment to work unconsciously influence the results, or that the patients who know that they are receiving a treatment can be subject to the placebo effect. Or that, when they return after 6 months to take the second cognitive test, the fact that they know the clinical team, the places, can reassure them; less stressed than the first time, they might get better test results, unrelated to the treatment.

To reduce these biases, clinical research uses so-called “randomized” studies. The participants are divided by lot into two groups (we speak of “arms”). In one, they receive the drug, in the other, a placebo. If there are biases in the study, they will be found in both arms.

The functional magnetic resonance imaging data, however, turned out to be consistent with these initial results: the neuroradiologists who analyzed them had never seen this. At that moment, we thought that something was indeed happening.

In fact, of the seven patients, six showed an improvement in their cognitive abilities of around 10 to 30%. Their 3D representation had improved, as had their ability to understand instructions and their attentiveness. The disparity observed in the results could be explained in particular by the fact that initially the cognitive performances of the patients were very diverse.

However, no improvement was observed in their sense of smell. However, this point is quite difficult to assess in patients affected by an intellectual disability.

The MRIs also revealed that some connections had been restored, particularly in the visual areas and in the sensorimotor cortex. The new cerebral "mapping" obtained after treatment proved to be closer to that of non-trisomic subjects 21. This corresponds well to the observed clinical improvements. Interestingly, these changes were also seen in the person whose cognitive test did not improve significantly.

TC: Do we know what happens after stopping treatment?

NP: No, we don't know yet. So far, only three patients have completed their 6 months without treatment. They took the cognitive test and the MRI again, but we won't have the analyzes of these new data until about 3 months from now.

However, one can speculate that there will probably be a decline. However, this remains to be confirmed.

TC: Do these results open a new therapeutic avenue to improve the lives of patients with Down syndrome?

NP: The testimonies of the entourage of some of the patients seem to attest to an improvement in their quality of life. But however encouraging these results and testimonials are, there is still a lot to be done to confirm this work.

We are now going to set up a larger clinical trial, recruiting 60 participants (this figure was determined by our statisticians on the basis of the results obtained during this first pilot study), including women. Importantly, this new trial will contain a randomized control arm, so that no one knows who is receiving GnRH and who is receiving placebo, neither the patients nor the members of the clinical team.

Let's be clear: if these preliminary results seem promising, we must remain very careful. This is not to say that GnRH could fully restore the cognitive abilities of people with trisomy 21. Indeed, although our work demonstrates that GnRH plays a role in cognition, this hormone is not, by far not the essential factor in human beings.

As proof, the vast majority of patients without Down syndrome who have a congenital problem of GnRH receptors generally do not present an intellectual disability. This suggests that compensation mechanisms exist.

PV: It should be understood that there are two scenarios with regard to GnRH deficiency. The receptor for the hormone may not be present at all early in life, such as in patients with congenital conditions. In this case, the brain probably adapts.

In other cases, such as trisomy 21, the GnRH system works correctly for a period of life, then begins to malfunction. The brain then fails to adapt, which triggers cognitive problems. In the individuals concerned, GnRH therefore seems to play a more important role in cognition than in those affected by a congenital deficiency. We've seen it in other work, in mice. By inhibiting, in normal mice, the receptors of GnRH neurons, these develop cognitive and olfactory deficiencies as pronounced as those of Down syndrome mice.

It is suspected that these mechanisms could also play a role in the pathological aging of the brain, or even in certain neurodegenerative diseases, such as Alzheimer's disease. Work is underway to clarify the role of GnRH in these scenarios.

One thing is certain: however important this neurohormone is, it is not a miracle molecule that would improve, restore or protect cognition, but rather an important piece of a complex hormonal puzzle. This work suggests that restoring, in patients with Down syndrome, the biological rhythm of its release as it exists in healthy people could make it possible to mobilize their cognitive reserve.

Vincent Prevot, Director of Research in Neuroendocrinology and Neurosciences, Inserm et Nelly Pitteloud, Professor at the University of Lausanne - Head of Department, Endocrinology, Diabetology and Metabolism at the Center hospitalier universitaire vaudois (ChuV), University of Lausanne

This article is republished from The Conversation under Creative Commons license. Read theoriginal article.