Autism Research: A Breath of Fresh Air

With all the words that are spilled and all the debates that rage over autism cause, cure, treatment and research there is little discussion, let alone effort, to actually find and prove new treatments and cures for autism disorders. It is a breath of fresh air to learn of some autism research that is actually being conducted with a view to HELPING autistic persons FUNCTION better. Such news is seldom heard.

One of the funders of the study is Autism Speaks which often takes heat from all sides in the world's autism communities. Well done Autism Speaks and other funding agencies involved in this effort. Hopefully more research aimed at actually helping autistic persons function better will be conducted in the near future.

Jill Cornfield at Autism Vox has highlighted research by Seaside Therapeutics LLC of a drug that may help autistic persons communicate better. The Seaside Therapeutics LLC press release indicates that it has received $30 million dollars in funding to conduct the study, which builds on the work of Seaside scientific founder Mark Bear of MIT, and explains the theory and aim of the study:

Historically, drug discovery in disorders of brain development has been unproductive largely due to the lack of mechanistic understanding of these disorders, as well as the absence of predictive animal models. Seaside Therapeutics is changing this paradigm through scientific exploration that focuses on identifying the fundamental pathophysiology of brain development disorders and applying this knowledge to develop targeted therapeutics. Recent discoveries by the Company's scientific founder, Mark Bear, Ph.D., Howard Hughes Medical Institute Investigator and Professor of Neuroscience at M.I.T., have revealed a molecular pathway, the mGluR5 signaling cascade, that is disrupted in a specific disorder of brain development - Fragile X Syndrome. With this knowledge, further research has provided insights for developing novel medications to normalize the function of this pathway, which Seaside believes may extend beyond Fragile X into a number of other developmental disorders, including autism.

STX209 is a selective gamma-amino butyric acid type B (GABA-B) receptor agonist. STX209 inhibits glutamate signaling in the brain and should thereby indirectly inhibit the excessive metabotropic glutamate receptor (mGluR) mediated protein synthesis implicated in Fragile X Syndrome. Preclinical studies using STX209 and other prototypic GABA agonists have demonstrated efficacy in animal models of Fragile X, suggesting that GABA agonists may provide significant benefits to people with Fragile X Syndrome and other disorders of brain development. STX209 entered a Phase 2 clinical study in adults and adolescents with Fragile X in December 2008 and a second trial in adolescents with autism spectrum disorders was initiated in March 2009. Seaside intends to expand both studies to include children as young as 6 years old during 2009. Data from both Phase 2 studies is expected in the first quarter of 2010.

STX107 is a highly potent, selective mGluR5 antagonist that was licensed from Merck & Company, Inc. STX107 was selected for development based on Dr. Bear's discovery of the connection between mGluR5 signaling and Fragile X Syndrome. Specifically, the evidence suggests that most, if not all, of the neurological and psychiatric consequences of Fragile X can be accounted for by exaggerated signaling through mGluR5 receptors. Preclinical research indicates that normalizing this exaggerated mGluR5 signaling reverses most of the anatomic, behavioral and synaptic abnormalities associated with Fragile X. By directly inhibiting exaggerated mGluR5 signaling, STX107 provides a compelling opportunity to treat core symptoms and disabilities of Fragile X Syndrome, autism and other developmental disorders. Seaside has been awarded translational research grants to support the development of STX107 from the National Institute of Mental Health, the National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke, Autism Speaks, FRAXA and the Best Pharmaceuticals for Children Act. STX107 is expected to enter Phase 1 clinical studies in healthy volunteers in October 2009.

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mGluR5 Spells Hope For Autism

Mark Bear, director of the Picower Institute and Picower Professor of Neuroscience (right), and Gül Dölen, a graduate student at Brown University,
report the correction of fragile X syndrome in mice. Photo / Donna Coveney

MIT News

Parents of autistic children have been preyed upon by purveyors of unproven treatments for their children's autism. But today there is hope, real hope, for autistic persons and the family members who care about their autistic children. Hope for an effective medical autism treatment is no longer something peddled by charlatans. We can now see it. We can even spell it. Hope for autism is spelled mGluR5.

mGluR5 is the shorthand for a metabotropic glutamate receptor. It was featured in the study led by Mark F. Bear, director of the Picower Institute and Picower Professor of Neuroscience at MIT published in the December 20 2007 edition of Neuron. The study by Professor's Bear's team supports the theory that many of FXS's (Fragile X's) psychiatric and neurological symptoms--learning disabilities, autistic behavior, childhood epilepsy--stem from too much activation of one of the brain's chief network managers, the metabotropic glutamate receptor mGluR5. As reported in MIT News:

Bear and colleagues study how genes and environment interact to refine connections in the brain. Synapses are the brain's connectors and their modifications are the basis for all learning and memory. There's a growing consensus among researchers that developmental brain disorders such as FXS, autism and schizophrenia should be considered "synapsopathies"--diseases of synaptic development and plasticity (the ability to change in response to experience).

Dendritic spines--little nubs on neurons' branchlike projections--receive many of the synaptic inputs from other neurons. Abnormal spines have long been associated with various forms of human mental retardation. In FXS, spines are more numerous, longer and more spindly than they should be. Thin spines tend to form weak connections.

The research team found that a 50 percent reduction in mGluR5 fixed multiple defects in the fragile X mice. In addition to correcting dendritic spines, reduced mGluR5 improved altered brain development and memory, restored normal body growth and reduced seizures--many of the symptoms experienced by humans with FXS.

The researchers used genetic engineering to reduce mGluR5, but a drug could accomplish the same thing. Although not yet approved by the FDA, mGluR5 blockers are entering into human clinical trials. "Insights gained by this study suggest novel therapeutic approaches, not only for fragile X but also for autism and mental retardation of unknown origin," Bear said.

As Christmas approaches families with autistic children may already have received our most wondrous gift of all - the knowledge necessary to provide an effective medical treatment for autism.

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MIT corrects inherited retardation, autism in mice

Wow! This could be the best autism news of all in the year of the Autism Knowledge Revolution.


MIT corrects inherited retardation, autism in mice

Research points to potential drug treatment

CAMBRIDGE, Mass.- Researchers at MIT's Picower Institute for Learning and Memory have corrected key symptoms of mental retardation and autism in mice.

The work, which will be reported in the Dec. 20 issue of Neuron, also indicates that a certain class of drugs could have the same effect. These drugs are not yet approved by the FDA, but will soon be entering into human clinical trials.

Fragile X syndrome (FXS), affecting 100,000 Americans, is the most common inherited cause of mental retardation and autism. The MIT researchers corrected FXS in mice modeling the disease. “These findings have major therapeutic implications for fragile X syndrome and autism,” said study lead author Mark F. Bear, director of the Picower Institute and Picower Professor of Neuroscience at MIT.

The findings support the theory that many of FXS's psychiatric and neurological symptoms-learning disabilities, autistic behavior, childhood epilepsy- stem from too much activation of one of the brain's chief network managers-the metabotropic glutamate receptor mGluR5.

“Fragile X is a disorder of excess-excess synaptic connectivity, protein synthesis, memory extinction, body growth, excitability-and remarkably, all these excesses can be reduced by reducing mGluR5,” said Bear, a Howard Hughes Medical Institute investigator.

Individuals with FXS have mutations in the X chromosome's FMR1 gene, which encodes the fragile X mental retardation protein, FMRP. The MIT study found that FMRP and mGluR5 are at opposite ends of a kind of molecular seesaw. They keep each other in check, and without FMRP, mGluR5 signals run rampant.

Bear and colleagues study how genes and environment interact to refine connections in the brain. Synapses are the brain's connectors and their modifications are the basis for all learning and memory. There's a growing consensus among researchers that developmental brain disorders such as FXS, autism and schizophrenia should be considered “synapsopathies”- diseases of synaptic development and plasticity (the ability to change in response to experience).

Dendritic spines--little nubs on neurons' branchlike projections-receive many of the synaptic inputs from other neurons. Abnormal spines have long been associated with various forms of human mental retardation. In FXS, spines are more numerous, longer and more spindly than they should be. Thin spines tend to form weak connections.

The research team found that a 50 percent reduction in mGluR5 fixed multiple defects in the fragile X mice. In addition to correcting dendritic spines, reduced mGluR5 improved altered brain development and memory, restored normal body growth, and reduced seizures-many of the symptoms experienced by humans with FXS.

The researchers used genetic engineering to reduce mGluR5, but the same thing could be accomplished by a drug. Although not yet approved by the FDA, mGluR5 blockers are entering into human clinical trials. “Insights gained by this study suggest novel therapeutic approaches, not only for fragile X but also for autism and mental retardation of unknown origin,” Bear said.

Earlier this year, MIT Picower Institute researcher Susumu Tonegawa and colleagues reported positive results using a different approach to reversing FXS symptoms. Tonegawa and colleagues identified a key enzyme called p21-activated kinase, or PAK, that affects the number, size and shape of connections between neurons.

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In addition to Bear, authors include Brown University graduate student Gul Dolen; Picower Institute postdoctoral fellow Emily Osterweil, B.S. Shankaranarayana Rao of the National Institute of Mental Health and Neuroscience in India; MIT graduate students Gordon B. Smith and Benjamin D. Auerbach; and Sumantra Chattarji of the National Center for Biological Sciences and Tata Institute of Fundamental Research in India.

This work is supported by the National Institute of Mental Health; the National Institute of Child Health and Human Development; the National Fragile X Foundation; FRAXA, a Fragile X research foundation; and the Simons Foundation.

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