@article{4d667aa1da2e4229908d3ffe79280d6c,
title = "Mechanism-based approaches to treating fragile X",
abstract = "Fragile X is the leading inherited cause of mental retardation and autism. Recent advances in our mechanistic understanding of the disease have led to the identification of the metabotropic glutamate receptor (mGluR) as a therapeutic target for the disease. These studies have revealed that core defects in multiple animal models can be corrected by down regulation of mGluR5 signaling. Although it remains to be seen if mGluR5 antagonists or related approaches will succeed in humans with fragile X, the progress in fragile X stands as a strong testament to the power of applying knowledge of basic neurobiology to understand pathophysiology in a genetically validated model of human psychiatric disease. These breakthroughs and several of the resulting drug development efforts are reviewed.",
keywords = "Autism, Fragile X, Fragile X mental retardation protein (FMRP), Long-term depression (LTD), Metabotropic glutamate receptor (mGluR), Plasticity",
author = "G{\"u}l D{\"o}len and Carpenter, \{Randall L.\} and Ocain, \{Timothy D.\} and Bear, \{Mark F.\}",
note = "Funding Information: The potent mGluR5 antagonist STX107 came from a portfolio of mGluR5 compounds discovered by scientists at Merck \& Co., Inc. A number of studies conducted at Merck highlighted the compound's desirable drug-like properties, as well as the ability to penetrate the blood{\textendash}brain barrier and bind mGluR5 receptors in the brain. After Seaside Therapeutics in-licensed the compound and demonstrated its efficacy in animal models of FX, it was then subjected to the battery of tests necessary to enable the filing of an investigational new drug (IND) application with the FDA. Included in those studies were in vitro studies such as genotoxicity assays (Ames test and chromosome aberration assay) and studies to address effects on an important cardiac ion channel (hERG). In vivo, dose-ranging and repeated-dose good laboratory practice (GLP) toxicology studies were conducted in rats and primates. The rat toxicology study design also incorporated an in vivo genotoxicity component (in vivo micronucleus assay) as well as a CNS safety study. Independently, cardiovascular (primate), respiratory (rat), and gastrointestinal (rat) safety studies were conducted. Seaside Therapeutics conducted these studies under a cooperative translational research grant with the NIH. Results from all studies were evaluated, the results were compiled in a full IND document that was approved by the FDA, and Phase 1 trials in normal human volunteers are ongoing ( http://clinicaltrials.gov/ct2/show/NCT00965432?term=fragile+x\&rank=20 ). A favorable profile of STX107 in normal human volunteers will allow progression into studies in subjects with FX. ",
year = "2010",
month = jul,
doi = "10.1016/j.pharmthera.2010.02.008",
language = "English (US)",
volume = "127",
pages = "78--93",
journal = "Pharmacology and Therapeutics",
issn = "0163-7258",
publisher = "Elsevier Inc.",
number = "1",
}