Article

Side effects of minocycline treatment in patients with fragile X syndrome and exploration of outcome measures

M.I.N.D. Institute, University of California at Davis Medical Center, USA.
American Journal on Intellectual and Developmental Disabilities (Impact Factor: 2.08). 09/2010; 115(5):433-43. DOI: 10.1352/1944-7558-115.5.433
Source: PubMed

ABSTRACT Minocycline can rescue the dendritic spine and synaptic structural abnormalities in the fragile X knock-out mouse. This is a review and preliminary survey to document side effects and potential outcome measures for minocycline use in the treatment of individuals with fragile X syndrome. We surveyed 50 patients with fragile X syndrome who received minocycline for at least 2 weeks and found that the most common reported side effect is gastrointestinal difficulty, including loss of appetite. The families reported an improvement in language and behavioral areas. Outcome measures in the design of future randomized clinical trials should include both behavioral and language measures. As with any other treatments, we emphasize that randomized clinical trials are needed to determine the efficacy of minocycline in fragile X syndrome.

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Available from: Andrea Schneider, Jul 31, 2015
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    • "High MMP-9 activity levels are also lowered by minocycline in fragile X syndrome patients (Dziembowska et al., 2013). Notably, minocycline has been tested in clinical trials to treat fragile X syndrome and shown to provide significant functional benefits (Paribello et al., 2010; Utari et al., 2010; Leigh et al., 2013). Matrix metalloproteinases have also been implicated in other forms of autism (Abdallah and Miche1, 2013). "
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    • "Following the results of studies that showed treatment with mGluR5 antagonists, including mavoglurant, could rescue several synaptic phenotypes in animal models (Choi et al. 2010; de Vrij et al. 2008; Levenga et al. 2011; McBride et al. 2005; Tucker et al. 2006; Yan et al. 2005), it was hypothesized that mavoglurant had the potential to treat the underlying pathophysiology of FXS, thus differing from current pharmacotherapy for FXS which is symptom-driven. Other agents targeting specific molecular pathways are in development for FXS (Table 3); these include RG7090 (RO4917523), another mGluR5 antagonist; STX209 (arbaclofen, R-baclofen), a γ-aminobutyric acid type B (GABA B ) receptor agonist (Berry-Kravis et al. 2012); and minocycline, a matrix metalloproteinase-9 antagonist (Bilousova et al. 2009; Leigh et al. 2013; Paribello et al. 2010; Utari et al. 2010). All of these agents aim to address the underlying pathology of FXS by targeting specific molecular pathways. "
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    ABSTRACT: Advances in understanding the underlying mechanisms of conditions such as fragile X syndrome (FXS) and autism spectrum disorders have revealed heterogeneous populations. Recent trials of novel FXS therapies have highlighted several challenges including subpopulations with possibly differential therapeutic responses, the lack of specific outcome measures capturing the full range of improvements of patients with FXS, and a lack of biomarkers that can track whether a specific mechanism is responsive to a new drug and whether the response correlates with clinical improvement. We review the phenotypic heterogeneity of FXS and the implications for clinical research in FXS and other neurodevelopmental disorders. Residual levels of fragile X mental retardation protein (FMRP) expression explain in part the heterogeneity in the FXS phenotype; studies indicate a correlation with both cognitive and behavioral deficits. However, this does not fully explain the extent of phenotypic variance observed or the variability of drug response. Post hoc analyses of studies involving the selective mGluR5 antagonist mavoglurant and the GABAB agonist arbaclofen have uncovered significant therapeutic responses following patient stratification according to FMR1 promoter methylation patterns or baseline severity of social withdrawal, respectively. Future studies designed to quantify disease modification will need to develop new strategies to track changes effectively over time and in multiple symptom domains. Appropriate selection of patients and outcome measures is central to optimizing future clinical investigations of these complex disorders.
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    • "Marker is shown on the left. in the fmr1 KO mouse establishes it as a potential pharmacotherapy for the treatment of FXS [Bilousova et al., 2009]. Although clinical studies have indicated that patients benefited from minocycline pharmacotherapy in a survey [Utari et al., 2010], open label [Paribello et al., 2010], and controlled trial [Leigh et al., 2013] molecular measures showing a clear biological response to minocycline have not been established. Here we report that MMP-9 activity is elevated in FXS as reported in the animal models [Bilousova et al., 2009; Siller and Broadie, 2011] and that minocycline can substantially lower the level of MMP-9. "
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    ABSTRACT: Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by lack of the FMR1 protein, FMRP, a translational repressor. Its absence leads to up-regulation of locally translated proteins involved in synaptic transmission and plasticity, including the matrix metalloproteinase-9 (MMP-9). In the Fmr1 knock-out (KO), a mouse model of FXS, an abnormal elevated expression of MMP-9 in the brain was pharmacologically down-regulated after treatment with the tetracycline derivative minocycline. Moreover, the rescue of immature dendritic spine morphology and a significant improvement of abnormal behavior were associated with down-regulation of MMP-9. Here, we report on high plasma activity of MMP-9 in individuals with FXS. In addition, we investigate MMP-9 changes in patients with FXS who have gone through a minocycline controlled clinical trial and correlate MMP-9 activity to clinical observations. The results of this study suggest that, in humans, activity levels of MMP-9 are lowered by minocycline and that, in some cases, changes in MMP-9 activity are positively associated with improvement based on clinical measures. © 2013 Wiley Periodicals, Inc.
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