FRAXA Research Foundation - finding a cure for Fragile X

Miklos Toth, Ph.D.
Principal Investigator
Ji-eun Oh, Ph.D.
Postdoctoral Associate
Weill Medical College
of Cornell University

Changes in the epigenetic status of genes have recently been implicated in several neurological and psychiatric diseases. Epigenetic changes such as DNA methylation (at CpG dinucleotides) and secondary histone modifications (i.e. acetylation and methylation) have physiological and behavioral consequences similar to genetic mutations but do not involve changes in the DNA sequence.

In the context of the fragile X syndrome, epigenetics has been limited to the study of the FMR-1 gene itself because its inactivation by DNA methylation triggers the onset of the disease. Here we hypothesize that epigenetic changes in fragile X are much more widespread because FMRP-1 is a translational inhibitor and could alter the expression of enzymes responsible for DNA methylation and histone modifications. Also FMRP binds a specific set of RNAs, called miRNAs, that are involved in epigenetic modifications. Therefore, absence of FMRP in fragile X could lead to genome-wide epigenetic modifications involving many genes with pathogenic roles in the disease. Reversing these epigenetic marks would represent a new strategy in the treatment of fragile X.

Funded from 2004-2006
Note 6/09: An exciting aspect of this project is that it evaluated an already approved drug. Based on the positive results of this study and additional confirming evidence, a trial of baclofen is now in progress in patients with Fragile X.

The absence of FMRP in fragile X syndrome, besides cognitive abnormalities, is associated with hyperactivity and heightened sensory sensitivity. The hyperactivity is similar to the behavioral abnormality seen in attention deficit disorders. The sensory hyper-reactivity is manifested as anxiety and sensory defensiveness to visual, tactile and auditory stimuli. Abnormal auditory processing in fragile X can underlie inattention, poor listening skill and difficulty in speech-understanding.

Some of the symptoms of fragile X can be reproduced in the FMRP deficient mouse strain. Indeed, FMRP deficient mice have constitutive hyperactivity and sensory hyper-reactivity manifested as abnormal sound induced reflexes and even seizures.

The aim of our research is to identify drugs that can correct behavioral abnormalities in FMRP deficient mice. Since both the hyperactivity and the sensory hyper-reactivity could be due to increased neuronal excitability, we tested if augmenting inhibitory neurotransmission, mediated by gamma-aminobutyric acid (GABA), alleviates these behavioral abnormalities. We have found that administration of the GABA(B) receptor agonist baclofen normalizes the hyperactivity of FMRP deficient mice. Although its use in the treatment of fragile X syndrome would be a new application, baclofen (Lioresal®) has long been used in and approved for the treatment of reversible spasticity in multiple sclerosis and severe spasticity in patients with spinal cord injury. These applications demonstrated a good safety profile for baclofen.

Importantly, FMRP deficient mice are more sensitive than normal animals to baclofen, and that allows the use of an otherwise suboptimal or ineffective dose to normalize the hyperactivity. Nevertheless, tolerance develops against baclofen and therefore we are currently testing additional drugs and drug combinations that are expected to induce less or no tolerance to the drug(s). An additional benefit of these combinations is that they reduce anxiety, a frequent symptom in fragile X. Based on these data, targeting the GABA system/GABA(B) receptors could represent a novel therapeutic approach in the treatment of fragile X syndrome.