In 1975, Professor Jerome Lejeune noted that patients with homocystinuria had physical characteristics opposite those observed in individuals with trisomy 21. They tend to be exaggeratedly tall and slender, whereas those with Down syndrome are usually shorter. Those with either pathology experience intellectual disability. Lejeune stated that: "In both conditions, there are differences that could come from opposite disturbances in the synthesis of special proteins rich in serine, proline and cysteine. "

Long before genome sequencing and solely based on his clinical observations, Lejeune hypothesized that the gene encoding the CBS (cystathionine beta-synthase) enzyme, was responsible for overexpression of methionine in those with trisomy 21, just as it is under-expressed in homocystinuria.

Indeed, the gene responsible for encoding the enzyme CBS, on chromosome 21, is overexpressed in patients with Down syndrome just as Lejeune suspected, and for that reason it is considered a candidate gene, i.e., at least in part responsible for intellectual disability in Down syndrome.

Animal models represent a useful way to study the relationship between genotype and phenotype, and for the identification of potentially useful molecules for therapies. An original mouse model was created with an extra copy of the CBS gene by the research team of Prof. Yann Herault (Director of Research at the National Center for Scientific Research in Strasbourg). These genetically engineered mice have learning and memory disorders, struggle with object recognition and exploration. The development of a rat model is being funded by the Jerome Lejeune Foundation, and should further enhance investigators research into the role of the CBS gene in intellectual disability.

In experimentation, different approaches have been used to demonstrate the scientific hypothesis that overexpression of CBS is, at least in part, responsible for intellectual disability. In one case, when the expression of CBS was reduced in mice, the disabilities were corrected. Trisomic mice that had only two active copies of the CBS gene, rather than three, were identical in behavior to those of wild type mice.

In a second approach, the overexpression of CBS, induced in the hippocampal and cortical regions (major areas of the brain involved in memory processes and learning) effectively disrupted the associative memory stimulated during object recognition in adult mice. This recent research shows that overexpression of CBS, due to an extra copy of chromosome 21 is sufficient to induce memory impairment in animal models, similar to those observed in the humans with Down syndrome.

Biochemical reactions related to the activity of CBS are very important for the metabolism of cells in the nervous system. The CiBleS21 program, initiated by the Jérôme Lejeune Foundation, aims to identify an inhibitor of the enzyme for CBS (cystathionine β-synthase).

Facts and Milestones

• - The CibleS21 program was designed and piloted by the Jérôme Lejeune Foundation under the direction of Dr. Henri Bléhaut, Director of Research, assisted by Francis Bellamy, PhD.
• - 2004: Launch of CiBleS21 international research program involving nearly twenty teams of researchers from both the academic and industrial sectors.
• - 2005: IDEALP then NovAliX pharmaceutical companies begin working in coordination with the Jérôme Lejeune Foundation.
• - 2011: The Jerome Lejeune Foundation patents a family of inhibitors for the CBS enzyme.

The CiBleS21 program is an ongoing research project fully funded by the Jerome Lejeune Foundation. The approximate of the program between 2004 and 2010 was $2.2 million. Annual funding continues at levels between $250,000 and $650,000.