Michalon A, Sidorov M, Ballard TM, Ozmen L, Spooren W, Wettstein JG, Jaeschke G, Bear MF, Lindemann L. Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. Neuron. 2012 Apr 12;74(1):49-56. PubMed.
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FRAXA Research Foundation
This work is an impressive confirmation of the metabotropic glutamate receptor (mGluR) theory of Fragile X syndrome, and it extends our understanding of the therapeutic mechanisms of this important new drug class. This is the first report of chronic treatment of this duration, made possible by this new agent (CTEP), which is significantly more potent and much longer acting than any other available research agent. Other studies have shown excellent preclinical efficacy later in (mouse) life, and studies of conditional knockout mice also strongly suggest that most symptoms of Fragile X are potentially reversible, but this article demonstrates that the kind of therapeutic intervention that we can realistically implement in patients is extraordinarily effective in reversing the major Fragile X phenotypes at all levels (cellular, synaptic, neural circuit, and whole animal/behavioral).
One of the past critiques of the mGluR5 antagonist treatment strategy for Fragile X was that some animal studies showed development of tolerance over the course of a few days of chronic treatment. One paper on which I was a coauthor (Yan et al., 2005) showed some tolerance, though we did not believe this was necessarily a predictor of human tolerance. No tolerance was seen with this long-term, high-level mGluR5 antagonism by CTEP, which bodes quite well for human clinical trials currently underway. CTEP also appears to be quite similar pharmacokinetically to the Roche drug currently under development for Fragile X, and this study appears to justify the use of long-half-life drugs that achieve steady antagonism of mGluR5. It is also remarkable that high-level antagonism of mGluR5 (well over 50 percent) results in no apparent adverse effects, in line with clinical observation of excellent tolerability of these drugs in patients. This is a powerful research tool, since far fewer administrations of drug are required in animal models—frequent administration of drugs results in powerful stress-related confounds in this type of chronic dosing study, and that was clearly absent here. CTEP will likely be in great demand for this use. Frequent drug administration and fluctuating drug levels are also problematic in clinical therapeutics as well, so this type of drug may be superior for many reasons, not least of which are adherence and efficacy.
There may be a great many potential uses for mGluR5 antagonists for a wide range of neuropsychiatric conditions. Clinical trials of this class in L-dopa-induced dyskinesia of Parkinson's disease (PD-LID) have been uniquely successful; this alone should justify marketing. This class also has great promise for the treatment of a broad range of addictions, and long-acting agents such as this would be ideal for this application. Of course, we are most intrigued by the potential of mGluR5 antagonists for treating other forms of autism spectrum disorders; it appears likely that some (though not all) cases of non-fragile-X-autism involve similar abnormalities in these same signaling pathways. Biomarkers such as APP may reveal individuals without the Fragile X mutation who also have hyperactive signaling similar to Fragile X (APP translation is known to be regulated by FMRP via mGluR, as Cara Westmark has shown (see ARF Webinar); Sokol et al. have shown elevated APP levels in a subset of autism patients—usually more severely affected individuals (Sokol et al., 2006). These individuals may be potential responders to this type of treatment. It is also possible that mGluR5 antagonists could be an effective component of a cocktail treatment for Alzheimer's disease, for example, by decreasing translation of APP while co-administration of a secretase inhibitor could reduce abnormal metabolism.
Intriguingly, Fatemi et al. recently published several postmortem studies suggesting that low levels of FMRP are associated with many different neuropsychiatric disorders—not just autism, but also Alzheimer's, schizophrenia, bipolar disorder, and other mood disorders (Fatemi et al., 2010). Decreased FMRP levels, from whatever primary cause, could lead to excessive signaling in these same pathways, and mGluR5 antagonists could be useful treatments in these cases. FMRP itself could end up as an important biomarker, even in cases other than developmental disorders
References:
Yan QJ, Rammal M, Tranfaglia M, Bauchwitz RP. Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology. 2005 Dec;49(7):1053-66. PubMed.
Sokol DK, Chen D, Farlow MR, Dunn DW, Maloney B, Zimmer JA, Lahiri DK. High levels of Alzheimer beta-amyloid precursor protein (APP) in children with severely autistic behavior and aggression. J Child Neurol. 2006 Jun;21(6):444-9. PubMed.
Fatemi SH, Kneeland RE, Liesch SB, Folsom TD. Fragile X mental retardation protein levels are decreased in major psychiatric disorders. Schizophr Res. 2010 Dec;124(1-3):246-7. PubMed.
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