More hopeful news for older individuals with neurodevelopmental disorders

Once again, there's been a signficant shift in scientific thinking about the fixed nature of brain development. The idea that the brain can't be changed after early childhood has been turned on its head in the past few years, and a new research study demonstrates how just how important that might be for the neurodevelopmental disorder, Fragile X syndrome (FXS). 

FXS is a genetic disorder, caused by disruption of a gene on the X-chromosome, that results in intellectual disability, behavioral problems, seizures and a high incidence of autism/autistic-like behaviors. [As a side note, a small percent of patients also exhibit hyperphagia and obesity, similar to PWS]. Fragile X has been the focus of intense research in recent years, and this has led to a good understanding of underlying genetic problem and its consequences - one major finding is that there is a significant over-activation of one particular neurotransmitter pathway in the brain, the mGlu5 pathway.  Apparently, the normal protein encoded by the FXS gene serves to dampen this pathway, and when it is nonfunctional, as in FXS, overactivity of the pathway results neural connections that are abnormally strong.  Several new drugs are being developed for FXS based on an understanding of the abnormal neurobiology in this disorder, and some have entered clinical trials [see previous blog and the FRAXA website for examples]. One pressing question, though, is whether these drugs will be of any use to those older individuals, whose brains have already developed under the influence of the these neurochemical disturbances.

A new paper out in the journal "Neuron" suggests that there is reason to be hopeful.  Using a well characterized mouse model, the authors [Michalon et al, 2012] gave a new, long acting Glu5 drug (a Glu5 inihibitor, CTEP) to FXS young adult mice who already exhibited the charactersitic features of FXS.  Administration of the drug at this point in their lives led to signficant reversal of FXS characteristics.  The mice were less susceptible to seizures, became less sensitive to noises, were less hyperactive, and got just about as smart as their normal mouse siblings.  The results suggest that many of the features of FXS may not be due so much to abnormal brain development, which might be much harder to fix, but rather to ongoing imbalances in brain transmission signals, which can be modified.  Similar findings have been shown in mouse models of Down syndrome - different neurodevelopmental disorder, different brain pathway disruption - but similar ability of a targeted drug to correct the brain imbalance in late adolescent animals already exhibiting signficant deficits.

Of course, we know from years of study that a mouse and a human are different animals - so there's no guarantee that humans will see equally impressive results compared to their mouse counterparts. Also, we are way behind in this game in the PWS world- we (and by 'we' I mean all the wonderful scientists working hard to understand PWS) still don't have great animal models nor a very good grasp of the underlying neurobiological problems in PWS. So there is much work left to be done.  However, there is definitely reason to be hopeful, even for those of us whose loved one with PWS is getting older more quickly than we ever imagined. The recent interest in developing treatments for these syndromes by pharamaceutical industry as well as knowing how quickly these drugs have advanced into clincal trials is heartening for sure.

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Topics: Research

Theresa Strong

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Theresa V. Strong, Ph.D., received a B.S. from Rutgers University and a Ph.D. in Medical Genetics from the University of Alabama at Birmingham (UAB). After postdoctoral studies with Dr. Francis Collins at the University of Michigan, she joined the UAB faculty, leading a research lab focused on gene therapy for cancer and directing UAB’s Vector Production Facility. Theresa is one of the founding members of FPWR and has directed FPWR’s grant program since its inception. In 2016, she transitioned to a full-time position as Director of Research Programs at FPWR. She remains an Adjunct Professor in the Department of Genetics at UAB. She and her husband Jim have four children, including a son with PWS.

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