Clinical trials for neurodevelopmental disorders: At a therapeutic frontier

Jeste, Shafali; Geschwind, Daniel H.

doi:10.1126/scitranslmed.aad9874

Cited by 52 publications

(42 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, as genetic testing in ASD and related neurodevelopmental disorders becomes clinical gold standard, an increasing number of children are diagnosed with genetic variants that not only will elucidate causal mechanisms but also therapeutic targets [50]. The identification of these targets necessitates quantifiable biomarkers that relate directly to genetic mechanisms.…”

Section: Discussionmentioning

confidence: 99%

A Quantitative Electrophysiological Biomarker of Duplication 15q11.2-q13.1 Syndrome

Frohlich

Şentürk²,

Saravanapandian

et al. 2016

PLoS ONE

Self Cite

View full text Add to dashboard Cite

BackgroundDuplications of 15q11.2-q13.1 (Dup15q syndrome) are highly penetrant for autism spectrum disorder (ASD). A distinct electrophysiological (EEG) pattern characterized by excessive activity in the beta band has been noted in clinical reports. We asked whether EEG power in the beta band, as well as in other frequency bands, distinguished children with Dup15q syndrome from those with non-syndromic ASD and then examined the clinical correlates of this electrophysiological biomarker in Dup15q syndrome.MethodsIn the first study, we recorded spontaneous EEG from children with Dup15q syndrome (n = 11), age-and-IQ-matched children with ASD (n = 10) and age-matched typically developing (TD) children (n = 9) and computed relative power in 6 frequency bands for 9 regions of interest (ROIs). Group comparisons were made using a repeated measures analysis of variance. In the second study, we recorded spontaneous EEG from a larger cohort of individuals with Dup15q syndrome (n = 27) across two sites and examined age, epilepsy, and duplication type as predictors of beta power using simple linear regressions.ResultsIn the first study, spontaneous beta1 (12–20 Hz) and beta2 (20–30 Hz) power were significantly higher in Dup15q syndrome compared with both comparison groups, while delta (1–4 Hz) was significantly lower than both comparison groups. Effect sizes in all three frequency bands were large (|d| > 1). In the second study, we found that beta2 power was significantly related to epilepsy diagnosis in Dup15q syndrome.ConclusionsHere, we have identified an electrophysiological biomarker of Dup15q syndrome that may facilitate clinical stratification, treatment monitoring, and measurement of target engagement for future clinical trials. Future work will investigate the genetic and neural underpinnings of this electrophysiological signature as well as the functional consequences of excessive beta oscillations in Dup15q syndrome.

show abstract

Section: Discussionmentioning

confidence: 99%

A Quantitative Electrophysiological Biomarker of Duplication 15q11.2-q13.1 Syndrome

Frohlich

Şentürk²,

Saravanapandian

et al. 2016

PLoS ONE

Self Cite

View full text Add to dashboard Cite

show abstract

“…The efficacy of mGluR5 antagonists and oxytocin, which showed promise in mouse models, is uncertain following clinical trials in humans 257–260 . It is unknown whether these failures are due to inadequate trial design and outcome measures, the lack of appropriate target engagement or simply choosing the wrong target 261 . It should be noted that the outcome measurements used in clinical trials are often not the same as those in animal models.…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

Advancing the understanding of autism disease mechanisms through genetics

Torre-Ubieta

Won

Stein

et al. 2016

Nat Med

726

609

View full text Add to dashboard Cite

Progress in understanding the genetic etiology of autism spectrum disorders (ASD) has fueled remarkable advances in our understanding of its potential neurobiological mechanisms. Yet, at the same time, these findings highlight extraordinary causal diversity and complexity at many levels ranging from molecules to circuits and emphasize the gaps in our current knowledge. Here we review current understanding of the genetic architecture of ASD and integrate genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology. Despite the challenges, these advances provide a solid foundation for the development of rational, targeted molecular therapies.

show abstract

“…These studies can provide an opportunity to reflect on future clinical trial design and implementation rather to conclude that these trials prove that a treatment is ineffective under all conditions or that the presumed underlying pathophysiological mechanisms are not valid [104]. Recent studies support also that derangement of the mGluR network may be responsible for increased rates of ASD seen in cytogenetically distinct forms of syndromic ASD ]105].…”

Section: Discussionmentioning

confidence: 99%

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

Budimirović¹,

Duy²

2015

Engrami

View full text Add to dashboard Cite

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.

show abstract

Clinical trials for neurodevelopmental disorders: At a therapeutic frontier

Abstract: A well-powered clinical trial that failed to replicate promising results in animal models of fragile X syndrome yields important lessons for clinical trial design (Berry-Kravis et al ., this issue).

Cited by 52 publications

References 9 publications

A Quantitative Electrophysiological Biomarker of Duplication 15q11.2-q13.1 Syndrome

A Quantitative Electrophysiological Biomarker of Duplication 15q11.2-q13.1 Syndrome

Advancing the understanding of autism disease mechanisms through genetics

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

Contact Info

Product

Resources

About