The therapeutic target against memory impairments in Down syndrome gains strength

In 2019, a research group led by Andrés Ozaita, of the Department of Medicine and Life Sciences at Pompeu Fabra University, described that mice models for Down syndrome have more cannabinoid receptor 1 (CBR1) in some regions of the brain. This anomaly affects the animals’ memory. Six years later, phase 1-2 clinical trials are now underway to test drugs that might correct these alterations in the memory of people living with the syndrome.

Now, a research team again led by Ozaita with the involvement of the Hospital del Mar Research Institute and the Neurological Tissue Bank of Hospital Clínic/IDIBAPS is expanding the knowledge concerning the therapeutic target described, demonstrating that in a mice model for Down syndrome, long-term pharmacological treatment improves memory alterations and inflammation. This finding paves the way for new clinical studies to explore a long-term treatment capable of counteracting the cognitive alterations associated with this syndrome and its age-related cognitive deterioration.

Down syndrome is the leading genetic cause of intellectual disability. It affects one in every thousand births. This means about 34,000 people in Spain and six million people around the world. This syndrome -–developed by people who have three copies of chromosome 21– especially affects the hippocampus, the region of the brain responsible for memory and learning. Thanks to advances in medicine, the life expectancy of people with Down syndrome has greatly increased, and it has been noted that trisomy 21 also causes Alzheimer’s disease. This means that, at 65 years of age, around 80% of people with Down syndrome show premature symptoms of dementia.

“For years we have been studying the alterations of the endocannabinoid system in different models of intellectual disabilities, especially those derived from Down syndrome”, explains Andrés Ozaita, director of the Cognition Biology Research Group of the UPF Department of Medicine and Life Sciences (MELIS), who led the study. “Now, we have seen that this system is altered in specific brain regions of people with Down syndrome and we have managed to confirm that, in mice modelled for the syndrome, a long-term experimental treatment improves cognitive behaviour”.

According to the study published today in the journal Alzheimer’s & Dementia, very specific regions of the hippocampus of people with Down syndrome have high levels of the cannabinoid 1 receptor. This receptor of the endocannabinoid system is involved in the proper functioning of neuronal connections, neuroinflammation and memory. 

This alteration, which they had already described in mice in 2019, improves substantially with long-term pharmacological treatment, from childhood to what would be equivalent to middle age in rodents, redressing their cognitive abilities.

“Using this therapeutic target has yielded positive results in young adult mice that reproduce some of the characteristics of Down syndrome, and now we see that it also works in middle age, when traits associated with neurodegeneration begin to appear”, asserts Anna Vázquez-Oliver, first author of the article. And she adds, “this experimental pharmacological intervention helps improve the memory of trisomic mice, but under no circumstances does it reverse the signs of neurodegeneration”.

The study also reveals that pharmacological treatment reverses morphological alterations of microglia –brain cells involved in the neuroinflammatory response typical of neurodegenerative diseases– and the presence of markers of inflammation in the plasma of the mice. “Although inflammation decreases, it is not completely reversed”, explains Ozaita, who adds: “We have endocannabinoid receptors in many organs of the body and we must continue to investigate in order to clarify whether this reduction in inflammation occurs only in the brain or also in other organs”.

The development of the treatment

Although the researchers are well aware that treating this target does not reverse all the effects of trisomy, they hope that “this finding will pave the way for improving the quality of life and independence of people with Down syndrome, even those who already have alterations due to neuronal degeneration”, Vázquez-Oliver affirms.

In this regard, the Hospital del Mar Research Institute, via the project Improving Condition in Down syndrome (ICOD, EU H2020 Research Programme), led by Rafael de la Torre –also one of the authors of this study– is conducting a phase 1-2 clinical study for the molecule AEF0217, developed by the French biotechnology company Aelis Farma. This molecule also acts on cannabinoid 1 receptors, and has already shown that a short treatment, of four weeks, in people with Down syndrome, is safe and improves key skills such as communication and social interactions of people with this condition.

Hence Ozaita is optimistic. “Based on what we can see in our study in mice, it seems plausible to develop a long-term treatment that will sustainably improve the quality of life of people with Down syndrome”. These improvements, he adds, “could also alleviate the alterations to the memory and the inflammation derived from premature Alzheimer’s that these people develop with age”.