Open-label add-on treatment trial of minocycline in fragile X syndrome

BMC Neurology (Impact Factor: 2.49). 10/2010; 10. DOI: 10.1186/1471-2377-10-91
Source: DOAJ

ABSTRACT Abstract Background Fragile X syndrome (FXS) is a disorder characterized by a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socio-emotional problems. It is hypothesized that the absence of the fragile X mental retardation protein (FMRP) leads to higher levels of matrix metallo-proteinase-9 activity (MMP-9) in the brain. Minocycline inhibits MMP-9 activity, and alleviates behavioural and synapse abnormalities in fmr1 knockout mice, an established model for FXS. This open-label add-on pilot trial was conducted to evaluate safety and efficacy of minocycline in treating behavioural abnormalities that occur in humans with FXS. Methods Twenty individuals with FXS, ages 13-32, were randomly assigned to receive 100 mg or 200 mg of minocycline daily. Behavioural evaluations were made prior to treatment (baseline) and again 8 weeks after daily minocycline treatment. The primary outcome measure was the Aberrant Behaviour Checklist-Community Edition (ABC-C) Irritability Subscale, and the secondary outcome measures were the other ABC-C subscales, clinical global improvement scale (CGI), and the visual analog scale for behaviour (VAS). Side effects were assessed using an adverse events checklist, a complete blood count (CBC), hepatic and renal function tests, and antinuclear antibody screen (ANA), done at baseline and at 8 weeks. Results The ABC-C Irritability Subscale scores showed significant improvement (p < 0.001), as did the VAS (p = 0.003) and the CGI (p < 0.001). The only significant treatment-related side effects were minor diarrhea (n = 3) and seroconversion to a positive ANA (n = 2). Conclusions Results from this study demonstrate that minocycline provides significant functional benefits to FXS patients and that it is well-tolerated. These findings are consistent with the fmr1 knockout mouse model results, suggesting that minocycline modifies underlying neural defects that account for behavioural abnormalities. A placebo-controlled trial of minocycline in FXS is warranted. Trial registration Open-Label Trial NCT00858689.

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Available from: Iryna M Ethell, Aug 17, 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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    • "№ improved 12 E 99.6 (3.38) p =0.003 p =0.007 p =0.03 Effect size 0.04 Citation Berry-Kravis et al. (2008) Leigh et al. (2013); Paribello et al. (2010) Erickson et al. (2011) Jacquemont et al. (2011) "
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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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