Hope for improving cognitive ability in people with Down syndrome

• Research HIV drug shows positive results for treating Down syndrome

Down

is the most common genetic cause of intellectual disability.

Caused by a trisomy on chromosome 21, one of the clinical manifestations associated with the syndrome is impaired cognitive ability.

With aging, nearly 80% of people with this condition develop Alzheimer-like symptoms.

At the moment, there is no effective treatment to alleviate the cognitive problems of these people, although it is an area in which different research groups are working.

A team of scientists from the University of Lille (France) and the University Hospital of Lausanne (Switzerland) has tested, with promising results, the usefulness of gonadotropin-releasing hormone (GnRH) therapy in

.

According to their data, the therapy brings improvements to cognitive function and brain connectivity.

Full details of the research are published in the journal

.

The scientists, led by María Manfredi-Lozano, started from recent findings showing that in addition to playing a key role in regulating reproductive function,

also has effects on cognition by acting on the brain's hippocampus.

To better understand this relationship, the researchers first studied the mechanism in mouse models of Down syndrome.

His studies in the laboratory showed that a network of

involved in the production of the hormone and found on chromosome 21 did not work correctly in the models studied, which produced abnormalities in the maturation of the neurons responsible for secreting GnRH.

These failures, the experiments showed, were directly linked in the animals with the cognitive deterioration - and the progressive loss of smell - characteristic of the syndrome.

To take the research a step further, the scientists tried to correct the deficient secretion of GnRH in the animals.

To do this, they turned to a

that is used in patients with GnRH deficiency, a rare disease that causes puberty not to occur spontaneously.

The therapy mimics the natural rhythm of hormone secretion.

And its administration resulted in an improvement in both cognitive function and olfactory ability in the trisomy mice.

With these good results in hand, the researchers wanted to see if the same benefits were obtained in humans.

They then launched a pilot trial with seven men with Down syndrome, whose ages ranged from 20 to 50 years.

Through a small pump placed in the arm, they were given a

.

Both before and after treatment, these people underwent cognitive and smell tests, as well as imaging tests of their brains.

According to the results published by

, in six of the seven men there was a moderate improvement in cognitive skills.

Benefits were seen in attention, episodic memory, reasoning, better understanding of instructions, and three-dimensional representation.

Imaging tests also showed an increase in neural connections.

In contrast, no improvement was seen in the sense of smell.

In their conclusions, the researchers emphasize that the data indicate that the treatment is effective in improving communication between different regions of the brain involved in cognition, learning and memory.

"GnRH pulse therapy holds out hope for improving cognitive deficits in Down syndrome, paving the way for future clinical trials," they point out in the scientific journal.

In a comment accompanying the research, Hanne M. Hoffmann, from the Department of Animal Science at Michigan State University (USA), points out the need to further study these mechanisms, as well as their possible usefulness in diseases where alterations in the neuronal function of GnRH, such as Alzheimer's, have also been observed.

More trials are needed to prove its efficacy

For

, leader of the Cellular and Systems Neurobiology laboratory and expert in Down syndrome at the Center for Genomic Regulation of Barcelona (CRG), although the results of the research are "interesting and promising", we must "be cautious in anticipate events because more clinical trials are needed to demonstrate its real clinical efficacy.

"There are a fairly large number of clinical trials going on right now to improve cognition in people with Down syndrome, some of which were successful when tested in a small number of individuals, but then failed when increasing the number of participants. Therefore,

, "he stresses.

On the other hand, Dierssen clarifies that, if its efficacy were finally shown, this therapy could not be used from the early stages of childhood, but, in any case, it would be applicable for cognitive deterioration that occurs in middle age.

"In principle, it would not seem convenient to apply it in childhood, in light of the results that are presented, since the deficiencies are observed later and we would also produce alterations in the development of the reproductive system."

Although the pilot clinical trial was only carried out in men, Dierssen considers its possible use in women to be plausible.

"In fact, the authors show deficiencies also in female mice, so it would make sense. It is true that these treatments are complicated in women of childbearing age, because they cannot be made to selectively affect regions related to cognition and therefore hormone levels would be affected.However, there are already clinical trials in women with mild-moderate Alzheimer's disease using a GnRH agonist, which demonstrated efficacy in a Phase II clinical trial in women with Alzheimer's disease who also received the acetylcholinesterase inhibitor donepezil," he explains.

For the expert, "the most interesting finding is the imbalance that the authors find in a complex network of microRNAs, which regulates the expression of GnRH and the maturation of GnRH neurons. Many previous studies have identified molecular mechanisms of hippocampal deficits in Down syndrome, and some have also shown positive results in clinical studies, but research has mainly focused on protein-coding genes, while we now know that there are other genomic regulatory elements that could also play a role in the disorders MicroRNAs are a class of RNAs that play important roles in regulating gene expression, and several of them are encoded by chromosome 21. Therefore,This work suggests that regulatory elements, such as microRNAs, may play a role in the neuropathology of Down syndrome."

Dierssen's team has just published a study showing that lamivudine, an antiretroviral used to control HIV,

"For now it is a preclinical investigation, but the advantage of lamivudine is that it is an already approved drug and it is also available as a generic pharmaceutical specialty, so the costs of research and development, although they are not zero, are much lower than those of a medicine that contains a newly approved drug. This means that we will very possibly be able to start clinical studies shortly," Dierssen says via email.

As to whether she believes that Down syndrome will be a long-term treatable condition, the researcher believes that, despite the difficulties involved, "advances in the field make us optimistic about the possibility of finding a therapeutic approach, which very probably involves changing the way clinical trials are carried out, and using precision and personalized medicine approaches, and e-health solutions that allow the effects of a treatment to be more effectively objectified. magic pills' and start incorporating multimodal interventions that address aspects such as cognitive stimulation, nutrition or physical exercise, in addition to testing drugs that can modulate cell signaling in key areas in a more holistic and complex way,"concludes.

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