Miklos Toth, Ph.D.
Principal Investigator
Weill Medical College
of Cornell University
Funded March 2006 for $60,000
Funded January 2004 for $50,000
An exciting aspect of this project is that it evaluates an already approved drug as a treatment for seizures --
and perhaps additional symptoms -- in Fragile X.
by Miklos Toth, 10/2006
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.