Autism is a highly heritable and often severe neurodevelopmental disorder, with no biomarkers of disease and no pharmacological intervention for core symptoms. The genetic basis in most patients is unknown and likely complex, however several simpler syndromes with known genetic mutations are strongly associated with autism, including those affecting the ras-MAPK signalling pathway. Drug discovery must be based on an understanding of the genetic, molecular, cellular or systemic basis of dysfunction. Without biomarkers of autism, we cannot develop etiologically relevant treatments. However, brain imaging has not yielded definitive results, brain tissue samples are difficult to obtain, and rodents cannot model the human-specific aspects. By generating induced pluripotent stem cells (iPSCs) and using these to create a neuronal model, we can analyze neuronal properties, such as growth and viability, signaling, and formation of synapses. We will develop an iPSC model from subjects with known mutations causing a ras-MAPK pathway syndrome, in order to identify biomarkers and enable drug screening for both rare syndromes and idiopathic autism.
Statement of Benefit to California:
Autism affects nearly 1% of children, and is a high priority concern in California. Affected individuals and families currently require a substantial amount of behavioral treatment and support for a lifelong and often incapacitating disability. Current research in model organisms suggest that other presumed neurodevelopmental disabilities can be reversed pharmacologically in adulthood, such as those associated with neurofibromatosis type I (NF1), which is strongly associated with autism. This proposal aims to identify biomarkers for autism by using rare disorders with known genetic mutations, such as NF1 and other disorders of the ras-MAPK signalling pathway. With the identification of biomarkers, identification of pharmacological treatments will be feasible.