High MMP‐9 activity levels in fragile X syndrome are lowered by minocycline

Dziembowska, Magdalena; Pretto, Dalyir; Janusz, Aleksandra; Kaczmarek, Leszek; Leigh, Mary Jacena; Gabriel, N; Durbin‐Johnson, Blythe; Hagerman, Randi J.; Tassone, Flora

doi:10.1002/ajmg.a.36023

Cited by 144 publications

(135 citation statements)

References 36 publications

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“…Moreover, patients with FXS may bottom out on rating scales depending on the severity of their phenotype. There has already been progress in developing questionnaires specifically graded to monitor changes in patients with FXS (41), and there is a movement toward objective measures to monitor treatment response such as studying ERPs as was carried out in the minocycline trial (57) or MMP-9 levels that were lowered in the minocycline trial (50). Upcoming trials are also studying combination therapy, as this may be another avenue toward unveiling beneficial effects of targeted treatments as well (NCT02642653, NCT02680379).…”

Section: Discussionmentioning

confidence: 99%

“…Additional studies are needed to evaluate ERP paradigms as an outcome measure that correlates with clinical improvement. In addition, MMP-9 levels in FXS are elevated in blood samples and minocycline lowered these levels in the minocycline trial (50). This measure also appears to be a good biomarker in FXS that can be used to monitor treatment response in future trials of minocycline and perhaps in the use of other targeted treatments for FXS.…”

Section: Minocyclinementioning

confidence: 95%

“…This dysregulation has also been associated with immature dendritic spine morphology (50,51). However, novel research in Fmr1/ Mmp-9 double KO mice revealed dendritic spines were similar to those in wild-type (wt) mice (52) suggesting MMP-9 is integral to the pathophysiology of FXSassociated defects at the neuronal level.…”

Section: Minocyclinementioning

confidence: 99%

“…Preclinical trials of minocycline in the Fmr1 KO mouse have induced mature dendritic spine morphology and improved anxiety and cognitive measures within one month of use (50,51). However, while positive results in behavior have been seen in both young and adult Fmr1 KO mice, research suggests younger mice have longer-lasting benefits, whereas improvements in adult mice disappear soon after cessation of treatment (53).…”

Section: Minocyclinementioning

confidence: 99%

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Review of targeted treatments in fragile X syndrome

Ligsay

Hagerman

2016

IRDR

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Section: Discussionmentioning

confidence: 99%

Section: Minocyclinementioning

confidence: 95%

Section: Minocyclinementioning

confidence: 99%

Section: Minocyclinementioning

confidence: 99%

See 2 more Smart Citations

Review of targeted treatments in fragile X syndrome

Ligsay

Hagerman

2016

IRDR

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“…For example, a phase 2 pilot placebo-controlled crossover trial of minocycline was carried out in children with FXS. The effect of this antibiotic that inhibits over expressed synaptic MMP-9 in FXS models showed mild global clinical improvement [92] and reduction of MMP-9 levels in the blood of responders [93]. As MMP-9 is over expressed in FXS, new unfolding compounds of relevance for reversing MMP-9 also hold promise such as eukaryotic translation initiation factor 4E (eIF4E) [94].…”

Section: Targeted Treatments In Fragile X Syndromementioning

confidence: 99%

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

Budimirović¹,

Duy²

2015

Engrami

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SummaryFragile X syndrome (FXS) is the leading known monogenetic cause of autism spectrum disorder (ASD) and inherited form of intellectual disability (ID). As the major and growing public health problem worldwide, ASD is purely behaviorally defined whereas FXS is a medical/genetic disorder characterized by ID and ASD in males and learning and behavioral/emotional problems (social anxiety, attention network) in both genders. FXS is caused by a mutation in the Fragile X Mental Retardation 1 gene (FMR1) that leads to the epigenetic silencing of the gene and absence of its encoded protein, the fragile X mental retardation protein (FMRP). FMRP selectively targets approximately 4% of the transcribed mRNAs in the brain. Namely, to date, 842 such target mRNAs in mammalian brains have been identified and many of them converge on the same pathway as nonsyndromic ASD. Thus, FXS is the most studied 'disorder of synapse' model for syndromic ASD in the field of neuroscience. There are currently no effective treatments for either FXS or ASD.In this review article, we discuss recent progress and future directions in translating breakthrough preclinical findings that reveal potential therapeutic targets into clinical trials for humans with FXS of potential relevance for ASD. To date, a total of 20 double-blinded, randomized, placebo-controlled clinical trials in FXS have been identified through the FDA ClinicalTrial.gov website. The majority of these trials were completed between 2008−2015. These mostly phase II trials in adults and adolescents tested 13 compounds and have primarily targeted excitatory/inhibitory imbalance theory of FXS and ASD, namely a reversal of social/behavioral symptoms that are part of the core FXS phenotype but not the core synaptic dysfunction in FXS. Despite much progress in the field propelled by the preclinical advances, these clinical studies illustrate the gaps and challenges of translating therapies from animal models to humans with FXS and ASD ('building a bridge and walking on it'). Specifically, recent challenges in the clinical trials demonstrate the need to study for longer period of time (6−12 months), prepubertal age group(s), develop more objective clinical outcome measures (i.e., clinician-based, relevant learning paradigms, and desired biomarkers), and longer placebo run-ins to minimize the placebo impact for both FXS and ASD. Ultimately, a truly satisfactory FXS, and ASD, therapy may likely involve a combination of drugs (and learning paradigms), each targeting a different aspect of the core synaptic, cognitive and behavioral impairments in FXS.

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Angelman syndrome: Current and emerging therapies in 2016

Tan¹,

Bird²

2016

American J of Med Genetics Pt C

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Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by a loss of the maternally-inherited UBE3A; the paternal UBE3A is silenced in neurons by a mechanism involving an antisense transcript (UBE3A-AS) at the unmethylated paternal locus. We reviewed all published information on the clinical trials that have been completed as well as the publicly available information on ongoing trials of therapies in AS. To date, all clinical trials that strove to improve neurodevelopment in AS have been unsuccessful. Attempts at hypermethylating the maternal locus through dietary compounds were ineffective. The results of an 8-week open-label trial using minocycline as a matrix metalloproteinase-9 inhibitor were inconclusive, while a subsequent randomized placebo-controlled trial suggested that treatment with minocycline for 8 weeks did not result in any neurodevelopmental gains. A 1-year randomized placebo-controlled trial using levodopa to alter the phosphorylation of calcium/calmodulin-dependent kinase II did not lead to any improvement in neurodevelopment. Topoisomerase inhibitors and antisense oligonucleotides are being developed to directly inhibit UBE3A-AS. Artificial transcription factors are being developed to "super activate" UBE3A or inhibit UBE3A-AS. Other strategies targeting specific pathways are briefly discussed. We also reviewed the medications that are currently used to treat seizures and sleep disturbances, which are two of the more common complications of AS. © 2016 Wiley Periodicals, Inc.

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High MMP‐9 activity levels in fragile X syndrome are lowered by minocycline

Cited by 144 publications

References 36 publications

Review of targeted treatments in fragile X syndrome

Review of targeted treatments in fragile X syndrome

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

Angelman syndrome: Current and emerging therapies in 2016

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