Scibx.2013.129

http://www.nature.com/scibx/journal/v6/n6/pdf/scibx.2013.129.pdf The team then tested the effects of lovastatin on electrophysiological excitability of brain tissue from Fmr1 knockouts. Brain slices from the visual cortex of Fmr1 knockout mice treated with lovastatin had a higher threshold of excitation than slices from vehicle-treated controls. Altogether, lovastatin made the brain slices of Fmr1 knockouts behave similarly to those from wild-type mice.
Lovastatin’s moderating effect on brain activity led to lower susceptibility to noise-induced seizures than vehicle.
By Lev Osherovich, Senior Writer
“Lovastatin could correct the excess protein synthesis in our mouse model of fragile X and could correct the audiogenic seizure phenotype Researchers at the Massachusetts Institute of Technology have mouse that’s a robust feature of this model,” said Bear.
data showing that the cholesterol drug lovastatin can correct fragile
The findings were reported in Neuron.
X syndrome.1 The findings add to a growing list of unconventional strategies for treating this common form of mental retardation.
Fragile X syndrome is caused by trinucleotide repeat expansions in The findings suggest statins could fit into to a treatment regimen for fragile X mental retardation 1 (FMR1). The condition causes alterations fragile X syndrome, but it is unclear whether the compounds could in protein synthesis in neurons, leading to work as monotherapy or as adjuncts to other developmental delays, autism and epilepsy.
FMR1’s normal function is to negatively regulate protein synthesis. Indeed, Fmr1 biosynthetic enzyme that is several steps knockout mice generally exhibit increased protein levels. Thus, therapeutic strategies molecules are fairly indirect inhibitors of for the condition have aimed to lower overall ERK-1 and ERK-2 activity. In contrast, brain rates of protein synthesis by hitting translation receptor antagonists are thought to hit fragile factors and brain receptors that regulate X–related translational mechanisms more Three companies—Novartis AG and Roche
and partner Seaside Therapeutics Inc.—
Randall Carpenter suggested statins could have clinical-stage compounds for fragile X prove useful in a subset of patients with syndrome that target such brain receptors.
fragile X syndrome that have severe seizures. “This paper was largely Now, a team led by Mark Bear, professor of neuroscience at focused on epileptogenesis and excitability in seizure models,” noted MIT and an investigator at the Howard Hughes Medical Institute, Carpenter. “About 20%–30% of people with fragile X mutations also
has shown that lovastatin can lower protein synthesis in the brain have a seizure disorder.”
and correct at least one mouse-specific manifestation of fragile X
Seaside and Roche are developing the biotech’s arbaclofen (STX- syndrome—epileptic seizures caused by loud noises.
209), a GABA receptor antagonist that is in two Phase III trials for fragile X syndrome and has completed a Phase II trial for autism spectrum disorder (ASD). Seaside will report the ASD data this year.
Bear’s team strung together prior evidence to formulate the hypothesis Seaside was cofounded by Bear and has not licensed his statin that statins could help treat fragile X.
In the 1990s, several teams showed that statins reduced Carpenter said it is not clear why some patients with fragile X have farnesylation of Ras and the activity of two downstream kinases, epilepsy and others do not, but Bear’s findings suggest statins could MAP kinase 3 (MAPK3; ERK-1) and MAPK1 (ERK-2), in cells.3 In be an add-on therapy for patients in the former camp.
2010, Bear’s team showed that blocking Ras-ERK-1/ERK-2 signaling Seaside and Roche also are co-developing RG7090, an antagonist decreased overall protein synthesis in a mouse model of fragile X.4 of metabotropic glutamate receptor subtype 5 (mGluR5; GRM5) that “What made us pursue lovastatin was that this is a widely used drug is in Phase II trials for fragile X syndrome. Seaside’s STX-107, another in clinical practice with a well-known safety profile that is even used mGluR5 antagonist, is in Phase II testing for fragile X.
in children,” said Bear.
Novartis’ AFQ056, another mGlur5 antagonist, is in Phase III trials His team found that brain tissue from Fmr1 knockout mice treated for fragile X.
with lovastatin had lower levels of active ERK-1 and ERK-2 and less Carpenter said GABA and mGluR5 are well-validated targets that protein synthesis than tissue from vehicle-treated controls. In cultured reduce the translation of a broad range of proteins and that it remains brain slices, lovastatin corrected the defective responsiveness to to be seen whether inhibiting Ras-ERK-1/ERK-2 signaling with statins electrical stimulus found in Fmr1 knockouts.
would have a comparably protective effect.
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Copyright 2013 Nature Publishing Group http://www.nature.com/scibx/journal/v6/n6/pdf/scibx.2013.129.pdf Indeed, because lovastatin had a big effect on audiogenic seizure but dose-ranging study of lovastatin in patients with fragile X who are only a modest effect on Ras-ERK-1/ERK-2 signaling, the compound 10–40 years old.
could be working through other mechanisms.
Lichter noted that besides fragile X syndrome, PAK1 is an attractive “It’s possible that lovastatin could be doing more than just inhibiting target in a range of inflammatory and cancer indications. Last month, ERK-1 and ERK-2—it depletes farnesylation in the brain, so there may Afraxis sold its portfolio of PAK1 inhibitors to Roche’s Genentech Inc.
be other targets,” said Bear.
unit. Genentech did not disclose its development plans for Afraxis’ He now plans to test lovastatin in other murine and tissue culture fragile X compounds.
assays of fragile X syndrome to see whether the compound affects the There are patents pending on the findings reported in Neuron, and cognitive aspects of the disease. He also plans to compare the efficacy the findings are available for licensing.
of statins with that of mGlur5 antagonists.
Osherovich, L. SciBX 6(6); doi:10.1038/scibx.2013.129 Carpenter said that instead of statins, it might be more effective to Published online Feb. 14, 2013 develop compounds that directly hit translational regulatory kinases REFERENCES 1. Osterweil, E.K. et al. Neuron; published online Jan. 23, 2013; Indeed, one such kinase—p21 protein (Cdc42 Rac)-activated kinase 1 (PAK1)—is the target of preclinical compounds from Afraxis Inc. for
Contact: Mark F. Bear, Massachusetts Institute of Technology, Carpenter said such strategies raise concerns about safety and 2. Bhakar, A.L. et al. Annu. Rev. Neurosci. 35, 417–443 (2012) selectivity because of the importance of these targets in the normal 3. Liao, J.K. & Laufs, U. Annu. Rev. Pharmacol. Toxicol. 45, 89–118 (2005)functioning of other tissues.
4. Osterweil, E.K. et al. J. Neurosci. 30, 15616–15627 (2012) Afraxis CEO Jay Lichter said ERK-1 and ERK-2 are likely to be COMPANIES AND INSTITUTIONS MENTIONED upstream of PAK1 in the kinase cascade that governs translation levels. He added that hitting this pathway indirectly with statins is an Genentech Inc., South San Francisco, Calif.
attractive option from a safety standpoint.
Howard Hughes Medical Institute, Chevy Chase, Md.
Massachusetts Institute of Technology “I don’t think an ethics board would have a problem giving this to Novartis AG (NYSE:NVS; SIX:NOVN), Basel, Switzerland Roche (SIX:ROG; OTCQX:RHHBY), Basel, Switzerland Along those lines, a Canadian team has started a small open-label Seaside Therapeutics Inc., Cambridge, Mass.
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Source: http://bearlab-s1.mit.edu/bearlab/pubs/scibx.2013.pdf