The long-term aim of this project is to translate genetic discoveries in humans with disorders of brain development into effective treatments for humans with these disorders. Human genetic studies have revealed that a common form of mental retardation known as fragile X syndrome (FXS) is a consequence of mutations in a single gene, FMR1, which prevents expression of a single protein (FMRP). Brain developmental in the absence of FMRP is associated with significant morbidity including impaired cognitive function, attention deficit and hyperactivity, anxiety, obsessive-compulsive and autistic behaviors. There are no effective treatments for fragile X syndrome. Understanding the effects of the fragile X mutation on brain development and function has been facilitated by generation of genetically engineered animals that model fragile X syndrome. The accumulated scientific evidence in these animal models over the last decade suggests that the symptoms of fragile X reflect excessive protein synthesis downstream of mGluR5, a metabotropic glutamate receptor. Genetic knockdown of mGluR5 expression can rescue multiple phenotypes in Fmr1 knockout mice. Moreover, acute and chronic treatment of fragile X mouse and fly models with mGluR5 antagonists in vivo has protected mutant animals from seizures, impaired cognitive function, and altered brain development. Thus, the evidence clearly indicates that mGluR5 is a valid target for development of drugs to treat fragile X.
The aim of our proposal is to advance an mGluR5 antagonist licensed from Merck into human clinical trials. Seaside Therapeutics has licensed from Merck several highly selective, potent and orally available mGluR5 antagonists and we intend to develop the lead compound, STX107, to treat FXS and, potentially autism. We request in this grant the funds needed to translate these compelling basic science discoveries into clinical research with the goal of providing meaningful treatments for FXS and other disorders of brain development. We will accomplish this by advancing our lead compound, STX107, through the preclinical studies necessary to fulfill FDA requirements to open an Investigational New Drug application and perform initial testing in humans. These studies provide the foundation that will allow us to test our hypothesis that mGluR5 antagonists can be an effective treatment of FXS and other disorders of brain development including autism. Relevance: Our research suggests for the first time a sound scientific rationale for pharmacologic treatment of fragile X syndrome and, potentially, other disorders of brain development such as autism. ? ? ?