Down syndrome: can intellectual disability of patients be treated?

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.

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 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.

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.

Anne Orliac