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Targeting the GABAB Receptor in Fragile X Syndrome and Autism Spectrum Disorders

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GABAB Receptor

Part of the book series: The Receptors ((REC,volume 29))

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Abstract

Fragile X syndrome (FXS) was long considered an immutable condition until the 1991 discovery of the causative genetic mutation, which enabled the basic research necessary to define the molecular pathophysiology. Understanding the disease biology was an essential step in identifying potential targeted treatments that are disease modifying. In FXS, the regulation of protein synthesis at the neuronal synapse is now thought to be a central pathway for pharmacologic intervention. Anecdotal evidence from a patient who received the GABAB agonist, baclofen, for the drug’s antispasmodic properties and found benefit for their autism lead to research focused on developing baclofen for the treatment of autism and FXS. Arbaclofen, the active enantiomer of baclofen, was tested in the FXS mouse model and shown to reverse many of the abnormal neuronal functions associated with FXS including reversing the abnormally elevated protein synthesis. The existing safety data on baclofen facilitated clinical development, and arbaclofen was tested in autistic and FXS patients in multiple large, controlled clinical trials. The results of these studies failed to show clinical benefit in the chosen outcome measures; however, the arbaclofen clinical trials contributed to the reevaluation of what success will look like for FXS patients. The FXS community has a renewed focus in developing sensitive and reliable outcome measures for future trials, with the ultimate goal of developing disease-modifying treatments.

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Authors and Affiliations

  1. Cydan Development, Cambridge, MA, 02139, USA

    Aileen Healy Ph.D.

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  1. Aileen Healy Ph.D.
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Correspondence to Aileen Healy Ph.D. .

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Editors and Affiliations

  1. Neuroscience Institute, National Research Council of Italy Neuroscience Institute, Cagliari, Italy

    Giancarlo Colombo

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Healy, A. (2016). Targeting the GABAB Receptor in Fragile X Syndrome and Autism Spectrum Disorders. In: Colombo, G. (eds) GABAB Receptor. The Receptors, vol 29. Humana Press, Cham. https://doi.org/10.1007/978-3-319-46044-4_13

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