Down syndrome : can intellectual disability of patients be treated ?
- Today, research is looking into the possibility of treating the intellectual disability associated with Down's syndrome.
- Scientists are showing that improving the quality of sleep of children with Down's syndrome promotes their intellectual and behavioural development.
- Screening for obstructive sleep apnoea syndrome from the age of 6 months would be particularly beneficial for the development of these children.
- Leucettinib-21 is a drug candidate for treating intellectual disability, which could correct the cognitive disorders associated with Down's syndrome or Alzheimer's disease.
- Even though there are more than 5 million people with Down's syndrome in the world and this research contributes to the treatment of other diseases, funding remains difficult.
Around 70,000 people1 in France are carriers of Trisomy 21 (T21), more commonly known as Down’s Syndrome, a genetic anomaly characterised by the presence in cells of an extra copy, more or less complete, of chromosome 21. The only known risk factor to date is the mother’s age, with an increased risk in the event of late conception, especially after the age of 40.
The presence of this extra chromosome disrupts the expression of certain genes, increasing the risk of physical abnormalities, such as muscular hypotonia and hyperlaxity of the ligaments, or certain malformations, most often curable, such as heart disease or digestive malformations.
This particularity also causes an intellectual impairment that varies greatly from one individual to another, generally ranging from mild to moderate. This reduction in intellectual performance affects the areas of conceptualisation, adaptation and communication ; on the other hand, people with Down’s syndrome are often very good at socialising. Down’s syndrome is also associated with premature ageing, with the development of dementia or Alzheimer’s disease, which can begin as early as the age of 35–40. In France, the life expectancy of a T21 carrier is now 60 years.
Treating sleep apnoea to improve intellectual development
Environment, education and co-morbidities play an important role in the cognitive development of children with Down’s syndrome. Professor Brigitte Fauroux has therefore turned her attention to a factor that could potentially exacerbate the decline in intellectual performance : sleep quality. “I had an idea that the intellectual developmental delay in children was exacerbated by undetected sleep apnoea from the very first months of life,” she explains. Obstructive sleep apnoea syndrome (OSA) is characterised by repeated closure of the upper airways during sleep, and poor-quality sleep punctuated by awakenings. OSA is particularly common in patients with Down’s syndrome, due to a lack of development of the middle part of the face and hypotonia of the upper airway dilator muscles.
During apnoea, the brain is deprived of oxygen, which is essential for good neurocognitive and behavioural development, particularly in young children. Current guidelines for monitoring children with chromosomal abnormalities recommend systematic screening for OSA using polysomnography, before the age of 4. “But as these recommendations are not based on scientific studies, the optimum time for screening and, if necessary, treatment of apnoea, remains unclear,” continues Brigitte Fauroux.
With funding from the Fondation Jérôme Lejeune, the researchers set out to assess the impact of early detection and treatment of OSA in children from the age of 6 months, the first time this type of study had been conducted anywhere in the world.
The team followed 40 infants who received polysomnography at home every 6 months, from the age of 6 months to 3 years. If OSA was diagnosed, treatment was provided at the Necker Hospital, and most often consisted of ENT surgery to treat upper airway obstruction. The neurocognitive development of these children was then assessed at the age of 3 and compared with that of a group of 40 3‑year-old children with Down’s syndrome who had received standard follow-up, but without the systematic sleep explorations. The results, published in The Lancet Regional Health – Europe in October 20242, reveal both the very high prevalence of OSA in children from the age of 6 months (39 of the 40 children concerned, 21 of whom had severe OSA), and a better intellectual and behavioural development in the children screened (with a median score of 55.4 on the Griffiths III global development test in the treated children compared with 50.7 for the ‘control’ group).
Screening for OSA from the age of 6 months with early treatment would therefore offer long-term benefits for the socio-emotional development, learning and communication skills of children with Down’s syndrome. However, diagnosis by polysomnography is tricky to implement on a large scale in such young children, and Brigitte Fauroux insists on the need to develop new diagnostic tools. “To be truly effective, we need reliable, non-invasive, inexpensive devices that can be used at home.”
A drug candidate to treat intellectual disability
A second promising avenue, this time to treat intellectual disability itself, takes us to Roscoff in Finistère, to the start-up Perha Pharmaceuticals. The company, half financed by public funds or foundations and half by private fund-raising, is working on a drug candidate, Leucettinib-21, which could correct both the cognitive problems associated with Down’s syndrome and those associated with Alzheimer’s disease3. “Several studies on mouse models have shown that the overactivity of the same gene located on chromosome 21, DYRK1A, is involved in both families of disorders,” explains Laurent Meijer, Chairman of Perha Pharmaceuticals and former Research Director at the CNRS. “We therefore looked for ways to reduce this activity, and ended up identifying a very promising molecule made by a marine sponge, Leucettamine B.”
The company went on to synthesise hundreds of derivatives of Leucettamine B to improve its characteristics, before coming up with Leucettinib-21, which is now protected by 4 patents. After the traditional tolerance/toxicity studies in animals, and the initial conclusive results on the molecule’s efficacy on the cognitive capacities of animal models, the drug candidate is currently undergoing phase 1 clinical trials to demonstrate its safety. 120 people are taking part in these trials, which will last until April 2025 : these include 96 healthy volunteers, 12 adults with Down’s syndrome and 12 Alzheimer’s patients. If the results are conclusive, phase 2 trials on children with Down’s syndrome could be carried out in 2026, to assess the impact on their cognitive development curve.
At the end of 2024, Bordeaux-based AelisFarma announced that it had obtained promising results from phase 1 / 2 trials on another drug candidate, AEF0217, which targets CB1 receptors, which control memory and cognition processes, as well as mood regulation. Phase 2 clinical trials are due to start in mid-2025.
Difficult to fund research
These results are all the more encouraging given that research aimed at correcting the intellectual disability associated with Down’s syndrome is still rare. “Society is very particularly on intellectual disabilities, and not many people are interested in Down’s Syndrome,” explains Laurent Meijer. Under the law, Down’s syndrome is one of the “particularly serious conditions, recognised as incurable at the time of diagnosis,” for which an abortion can be carried out, up to the last day of pregnancy. France is one of the countries where prenatal screening for Down’s syndrome is most common : in 2021, more than 90.9% of pregnant women were screened, according to an Inserm report4.
A 2008 study showed that, in the Paris region, nearly 95% of pregnancies in which Down’s Syndrome was detected resulted in a termination5. “This means that most of the people we talk to believe that Down’s syndrome is not a problem, because screening is available and in the vast majority of cases lead to termination of the pregnancy. Yet there are more than 5 million Down’s syndrome cases in the world. And Down’s syndrome opens the door to treatments for diseases that affect the general population, such as Alzheimer’s disease, diabetes, myocardial infarction and various types of leukaemia. However, finding funding for research into Down’s syndrome remains very difficult,” concludes Laurent Meijer. It is estimated that one foetus in 700 carries T21.
