Autism is a life-long disorder that affects nearly one in every 100 children born today. The severity of this disorder can have a profound effect on the child's ability to learn, communicate, and integrate into society, often leading to a tremendous cost and care burden for families with an affected child. Caring for all people with autism costs an estimated $35 billion per year in the United States alone. This figure comes from a study by Michael Ganz, an Assistant Professor of Society, Human Development, and Health at Harvard School of Public Health, who authored a chapter in the book, "The Costs of Autism," in the newly published book, "Understanding Autism: From Basic Neuroscience to Treatment" (CRC Press, 2006). Some claim this number is an underestimate of the true cost. Needless to say, autism has a profound effect on society and anything that is identified that can ameliorate autism symptoms will have a profound positive impact on society. Recent advances in genetic analyses have led to the identification of over 250 autism susceptibility genes that have been compiled in the Simons Research Foundation Gene list. At first glance this list might appear daunting as it suggests an incredible number of ways that genetic impairments can lead to autism, suggesting that any treatments that are identified might only impact a very small number of patients. This concern, however, may not be the case as many of the autism susceptibility genes can be placed in biochemical pathways that have been identified from basic research. The research proposed in this project focuses on Fragile X syndrome. Fragile X Syndrome in caused by the loss of FMR1 gene function and has an incidence rate of 1 in 3,000 children. Clinical evaluation of Fragile X patients has revealed that 30%-50% are clinically diagnosed with autism. This statistic reveals that Fragile X is the most common genetic cause of autism, accounting for 35% of all cases. In our proposed studies, we will use Drosophila and mouse models of Fragile X. In our studies, we find that the loss of the fmr1 gene function in our models leads to the alteration of pathways that include several other autism susceptibility genes. Our hope is that our studies will not only point to treatments of Fragile X, but also reveal potential treatments for other forms of autism. In previous studies, we have found that our Drosophila Fragile X model displays several defects that are analogous to those found in the mouse Fragile X model and in patients with this disorder. This includes social, memory, and neuroanatomical defects. In subsequent studies, we have found that these defects can be rescued by treating the flies with compounds that reduce the activity of a metabotropic glutamate receptor (mGluR). These "mGluR antagonists" have been shown to also reverse defects in the mouse model as well, and in fact are currently being tested in clinical trials with Fragile X patients. A recent finding shows that the mGluR signaling pathway is connected to another signaling pathway called the mTOR pathway. This link between the mGluR and mTOR signaling pathways contains several other autism susceptibility genes such as Tuberous Sclerosis I and II, Neurofibromatosis, PTEN, and RubinsteinTaybi's. This may mean that these forms of autism, and possibly others, affect this biochemical pathway and thus may respond to similar treatments. In this study, we will first test the efficacy of several drugs that target members of this new biochemical pathway to determine if they can rescue some of the defects observed in our Drosophila Fragile X model. If successful, these compounds will be tested in the mouse Fragile X model with the hope that they will rescue defects displayed by this model as well. We propose that the treatments we identify as being efficacious in both models will be prime candidate therapies to test in clinical trials with Fragile X patients.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
