“Fragile” hope for autism

In chapter 9 (“Reasons for Optimism”) of my book I discuss startling results obtained with various mouse models of genetic disorders that display some autism symptoms. That is, in mice carrying the fragile X syndrome (FXS), Rett syndrome or tuberous sclerosis genetic mutations or lesions, researchers were able to ameliorate abnormal, autism-like behaviors with interventions applied during adolescence or even in adulthood. That is, despite the fact that these mice had developed abnormally during fetal and early postnatal life, they could be treated successfully much later. Several new papers support this finding even further. FXS is a leading cause of mental retardation in children and involves unusual physical abnormalities. As many as 30% of FXS subjects also display features of autism. Genetic models of FXS also display some autism-like symptoms such as repetitive behaviors and social interaction deficits. A new paper shows that chronic treatment of these mice during adolescence and into adulthood with a drug candidate that blocks a receptor for the excitatory glutamate receptor, termed mGluR5, prevents the development of several abnormal behaviors (although the cardinal autism-like behaviors were not tested). Moreover, in two inbred mouse strains that display these autism-lke behaviors, blocking this same receptor with different drugs enhances social interaction and reduces repetitive behaviors. Although no major negative effects were observed in treating control mice in these experiments, it is very difficult to rule out cognitive side effects in mice. These, and prior results in the genetic FXS model led the biotech startup, Seaside Therapeutics, as well as two big pharma companies, Roche and Novartis, to begin testing their respective mGluR5 drugs in clinical trials for FXS. The hope is that efficacy with the rare FXS condition will lead to testing in the far more common disorder of autism.

A paper in last week’s Nature presented a different but intriguing result in a different genetic mouse model. Mutations in the gene SHANK2 are associated with autism spectrum disorders, and mice carrying this human microdeletion exhibit reduced  social interaction and verbal communication (see my prior post on ultrasonic vocalizations), and enhanced repetitive grooming and jumping. Treatment of these mice with a drug that activates mGluR5 markedly enhances social interaction, but does not affect the abnormal jumping or anxiety-like behaviors. The social interaction finding does not appear to be consistent with the results with the FXS mice, but different manipulations were used in each case, so it is difficult to compare the experiments using these different genetic models. Nonetheless, the upshot is that even late interventions can have positive effects on behavior in a variety of mouse models.

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2 Responses to “Fragile” hope for autism

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