There are exciting new developments occurring in finding potential new treatments for the fragile X syndrome, and by extension for autism. The fragile X syndrome, an X chromosome-linked syndrome and the most commonly inherited condition associated with intellectual deficiency, is considered to be the leading genetic cause of autism and autism spectrum disorders (ASD). Approximately 60% of males diagnosed with fragile X syndrome meet the criteria for autism or PDD-NOS, while among untested children with ASD 2 – 8% test positive for fragile X (Harris et al., 2008). The fragile X syndrome is due to the silencing of the fragile X gene, FMR1, and the lack of production of the fragile X protein, FMRP. This protein modulates the expression of a limited set of other genes that appear to be involved with neuronal plasticity and synaptic connections.
In a mouse model of fragile X, there is abnormal hyperactivity and seizure susceptibility due to over-activity of the excitatory glutamic acid neuro-transmitter pathway (Bear et al., 2004; Dolen et al., 2007). We and Dr. Frank Kooy’s lab in Belgium have also found there is reduced activity of the inhibitory GABA (gamma aminobuteric acid) pathway (El Idrissi et al., 2005; D’Hulst et al., 2006). These abnormalities in the brain of the mouse model of fragile X syndrome offer potential therapeutic targets for the fragile X syndrome. Because of the overlapping aspects of fragile X and autism, they may also be of benefit for at least a subset of subjects with ASD.
Basic research on the mouse model has led to the discovery that certain drugs that partially block some of the glutamate receptors in the brain produce dramatic improvements in the mice (Yan et al., 2005). Also, drugs that stimulate the inhibitory GABA pathway reduce seizure susceptibility in the mouse (Pacey et al., 2009). Now, double blind trials are underway at our Institute’s fragile X clinic and nine other fragile X clinics in humans with fragile X and also in subjects with ASD using a purified form of the GABAergic drug Baclofen (known as STX209 or R-baclofen; see www.clinicaltrials.gov) sponsored by the Seaside Therapeutics Corporation (www.seasidetherapeutics.com). Results of potential benefits from this new drug formulation should be known by later this year. Also, initial phase I human trials are beginning with drugs that partially block the Glutamate receptor (STX107) and if proven safe and effective should lead to comprehensive clinical testing. Another drug that partially blocks glutamate receptors, Fenobam, has undergone a successful open label phase I trial in fragile X subjects as well (Berry-Kravis et al, 2009).
Another potential treatment for fragile X is receiving widespread interest in the fragile X community. It was discovered that a commonly prescribed antibiotic, minocyline, could produce dramatic improvements in brain function and behavior in the mouse model of fragile X (Bilousova et al. 2009). Minocyline appears to inhibit a brain enzyme, MMP9, which is over-expressed in fragile X mice. Controlled clinical trials are just beginning for minocyline supported by FRAXA (www.FRAXA.org) and by the National Fragile X Foundation (www.NFXF.org). The hope is that some of these new targeted therapeutic drugs, if they work for fragile X, may also have important therapeutic benefits for some children with ASD.
A Fragile X Clinical and Research Consortium (FXCRC) was initiated in 2006 by the National Fragile X Foundation (NFXF) to advance clinical practice and facilitate coordinated, collaborative multi-site research on the fragile X syndrome. With support of the National Center on Birth Defects and Developmental Disabilities (NCBDDD) and the Centers for Disease Control and Prevention (CDC), the FXCRC has expanded to include 20 Fragile X Syndrome clinics in the U.S. and one in Canada (For locations see www.NFXF.org). The Institute for Basic Research (IBR), located on Staten Island, NY, is the site of one of the Fragile X clinics and is coordinating the CDC supported project that will speed research into emerging treatments for Fragile X syndrome and bring better care to the more than 100,000 Americans affected by the condition. In addition to IBR, collaborators in the project consist of the NFXF; the Association of University Centers on Disabilities (AUCD), and the Data Coordinating Center at Columbia University.
- Ted Brown, MD, PhD, is the Director of the New York State Office of Mental Retardation and Developmental Disabilities’ Institute for Basic Research and its George A. Jervis Clinic located on Staten Island, New York.
References
Bear, M.F., Huber, K.M., & Warren, S.T. (2004). The mGluR theory of fragile X mental retardation. Trends in Neuroscience, 27, 370-377.
Berry-Kravis, E., Hessl, D., Coffey, S., Hervey, C., Schneider, A., Yuhas, J., Hutchison, J., Snape, M., Tranfaglia, M., Nguyen, D.V., & Hagerman, R. (2009). A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. Journal of Medical Genetics, 46, 266-271.
Bilousova, T.V., Dansie, L., Ngo, M., Aye, J., Charles, J.R., Ethell, D.W., & Ethell, I.M. (2009). Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. Journal of Medical Genetics. 46, 94-102.
Dölen, G., Osterweil, E., Rao, B.S., Smith, G.B., Auerbach, B.D., Chattarji, S., & Bear, M.F. (2007). Correction of fragile X syndrome in mice. Neuron, 56, 955-962.
D’Hulst, C., De Geest, N., Reeve, S.P., Van Dam, D., De Deyn, P.P., Hassan, B.A., & Kooy, R.F. (2006). Decreased expression of the GABAA receptor in fragile X syndrome. Brain Research, 1121, 238-245.
El Idrissi, A., Ding, X., Scalia, J., Trenkner, E., Brown, W.T., & Dobkin, C. (2005). Decreased GABA(A) receptor expression in the seizure-prone fragile X mouse. Neuroscience Letters, 377, 141-146.
Harris, S.W., Hessl, D., Goodlin-Jones, B., Ferranti, J., Bacalman, S., Barbato, I., Tassone, F., Hagerman, P.J., Herman, H., & Hagerman, R.J. (2008). Autism profiles of males with fragile X syndrome. American Journal of Mental Retardation, 113, 427-438.
Pacey, L.K., Heximer, S.P., & Hampson, D.R. (2009). Increased GABA(B) receptor-mediated signaling reduces the susceptibility of fragile X knockout mice to audiogenic seizures. Molecular Pharmacology. 76, 18-24.
Yan, Q.J., Rammal, M., Tranfaglia, M., & Bauchwitz, R.P. (2005), Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology, 49, 1053-1066.
