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Fragile X syndrome is a genetic disorder that can lead to a wide range of developmental, physical and behavioral problems; these include mild to moderate intellectual disability, such changes to the face and body as an unusually long narrow face, and such features of autism as problems with social interaction and delayed speech.
The gene responsible is known: the syndrome (FXS) occurs as a result of a mutation in the fragile X mental retardation 1 (FMR1) gene. This results in the insufficient production of a protein called FMR, which is required for the normal development of connections between neurons and for brain development.
Prof. Irit Sagi of the Weizmann Institute’s Biological Regulation Department research a family of “Pac-Man-like” enzymes – matrix metalloproteinases (MMP) – which degrade proteins and extracellular matrix in normal physiological processes; and her team developed a drug that specifically blocks the activity of one of them -- MMP9 – which is known to be highly expressed in the brain, especially in fragile X. Working together with collaborators, they found that blocking MMP9 attenuates autism-like behaviors in mice. With funding from the Azrieli Foundation, the scientists are now exploring why their specific drug has this impact on mouse behavior, as well as developing novel experimental strategies for designing mechanism-based therapeutics to target MMP9 and its tissue-specific substrates within the microenvironment of single neurons in both FXS mice models and human tissue cultures.
“Maybe MMP9 does not ‘drive’ the disease, but our findings suggest that it is definitely a major factor in the symptoms of this genetic disorder. We believe that if we can reduce the harmful activity of MMP9, maybe we can attenuate the symptoms of fragile X syndrome, including, possibly even the autism-like behavior,” says Sagi.
Prof. Irit Sagi's research is supported by the Helen and Martin Kimmel Institute for Stem Cell Research, the Moross Integrated Cancer Center; the Azrieli Foundation; the Mireille and Murray Steinberg Family Foundation; Leesa Steinberg; the Leonard and Carol Berall Post-Doc Fellowship for Research on Autoimmune Diseases including Crohn's; the Rising Tide Foundation; Cynthia and Andrew Adelson; Gordon S. Oppenheimer; John Rose; Samuel Cohen-Scali; and the European Research Council. Prof. Sagi is the incumbent of the Maurizio Pontecorvo Professorial Chair.