Advancing clinical development for neuronopathic Hunter syndrome through a quantitatively-driven reverse translation framework.

A quantitatively-driven evaluation of existing clinical data and associated knowledge to accelerate drug discovery and development is a highly valuable approach across therapeutic areas, but remains underutilized. This is especially the case for rare diseases for which development is particularly challenging. The current work outlines an organizational framework to support a quantitatively-based reverse translation approach to clinical development.

Seizure reduction in TSC2-mutant mouse model by an mTOR catalytic inhibitor.

Objective: Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by autosomal-dominant pathogenic variants in either the TSC1 or TSC2 gene, and it is characterized by hamartomas in multiple organs, such as skin, kidney, lung, and brain. These changes can result in epilepsy, learning disabilities, and behavioral complications, among others. The mechanistic link between TSC and the mechanistic target of the rapamycin (mTOR) pathway is well established, thus mTOR inhibitors can potentially be used to treat the clinical manifestations of the disorder, including epilepsy.

GENE TARGET: A framework for evaluating Mendelian neurodevelopmental disorders for gene therapy.

Interest in gene-based therapies for neurodevelopmental disorders is increasing exponentially, driven by the rise in recognition of underlying genetic etiology, progress in genomic technology, and recent proof of concept in several disorders. The current prioritization of one genetic disorder over another for development of therapies is driven by competing interests of pharmaceutical companies, advocacy groups, and academic scientists. Although these are all valid perspectives, a consolidated framework will facilitate more efficient and rational gene therapy development.

Shifted phase of EEG cross-frequency coupling in individuals with Phelan-McDermid syndrome.

Background: Phelan-McDermid Syndrome (PMS) is a rare condition caused by deletion or mutation of the SHANK3 gene. Individuals with PMS frequently present with intellectual disability, autism spectrum disorder, and other neurodevelopmental challenges. Electroencephalography (EEG) can provide a window into network-level function in PMS.

Phenotypic Screen with TSC-Deficient Neurons Reveals Heat-Shock Machinery as a Druggable Pathway for mTORC1 and Reduced Cilia.

Tuberous sclerosis complex (TSC) is a neurogenetic disorder that leads to elevated mechanistic targeting of rapamycin complex 1 (mTORC1) activity. Cilia can be affected by mTORC1 signaling, and ciliary deficits are associated with neurodevelopmental disorders. Here, we examine whether neuronal cilia are affected in TSC.

Tau: A Novel Entry Point for mTOR-Based Treatments in Autism Spectrum Disorder?

Dysregulation of the PI3K/Akt/mTOR pathway has become a point of convergence in autism spectrum disorder (ASD). In this issue of Neuron, Tai et al. (2020) identify a therapeutic role for tau reduction in downregulating this pathway and ameliorating ASD-like symptoms.

Auditory Processing of Speech and Tones in Children With Tuberous Sclerosis Complex.

Individuals with Tuberous Sclerosis Complex (TSC) have atypical white matter integrity and neural connectivity in the brain, including language pathways. To explore functional activity associated with auditory and language processing in individuals with TSC, we used electroencephalography (EEG) to examine basic auditory correlates of detection (P1, N2, N4) and discrimination (mismatch negativity, MMN) of speech and non-speech stimuli for children with TSC and age- and sex-matched typically developing (TD) children. Children with TSC (TSC group) and without TSC (typically developing, TD group) participated in an auditory MMN paradigm containing two blocks of vowels (/a/and/u/) and two blocks of tones (800 Hz and 400 Hz).

A framework for the investigation of rare genetic disorders in neuropsychiatry.

De novo and inherited rare genetic disorders (RGDs) are a major cause of human morbidity, frequently involving neuropsychiatric symptoms. Recent advances in genomic technologies and data sharing have revolutionized the identification and diagnosis of RGDs, presenting an opportunity to elucidate the mechanisms underlying neuropsychiatric disorders by investigating the pathophysiology of high-penetrance genetic risk factors. Here we seek out the best path forward for achieving these goals.

Electrographic spikes are common in wildtype mice.

High-voltage rhythmic electroencephalographic (EEG) spikes have been recorded in wildtype (WT) rats during periods of light slow-wave sleep and passive wakefulness. The source of this activity is unclear but has been attributed to either an inherent form of absence epilepsy or a normal feature of rodent sleep EEG. In contrast, little is known about epileptiform spikes in WT mice.

A unified circuit for social behavior.

Recent advances in circuit manipulation technologies have enabled the association of distinct neural circuits with complex social behaviors. The brain areas identified through historical anatomical characterizations as mediators of sexual and parental behaviors can now be functionally linked to adult social behaviors within a unified circuit. In vivo electrophysiology, optogenetics and chemogenetics have been used to follow the processing of social sensory stimuli from perception by the olfactory system to valence detection by the amygdala and mesolimbic dopamine system to integration by the cerebral and cerebellar cortices under modulation of hypothalamic neuropeptides.

The Way Forward for Mechanism-Based Therapeutics in Genetically Defined Neurodevelopmental Disorders.

Rare genetically defined neurodevelopmental disorders with increased risk of autism have recently become an entry point for autism-related drug discovery. Through exploration of downstream effects of the pathological mutations, specific mechanistic pathways have been identified as dysregulated. The identification of shared mechanisms across forms of autism opens the door for the development of novel "mechanism-based therapeutics.

Hyperactivity and Hypermotivation Associated With Increased Striatal mGluR1 Signaling in a Shank2 Rat Model of Autism.

Mutations in the family of genes have been consistently identified in genetic and genomic screens of autism spectrum disorder (ASD). The functional overlap of with several other ASD-associated genes suggests synaptic dysfunction as a convergent mechanism of pathophysiology in ASD. Although many ASD-related mutations result in alterations to synaptic function, the nature of those dysfunctions and the consequential behavioral manifestations are highly variable when expressed in genetic mouse models.

mGluR5 Modulation of Behavioral and Epileptic Phenotypes in a Mouse Model of Tuberous Sclerosis Complex.

Drugs targeting metabotropic glutamate receptor 5 (mGluR5) have therapeutic potential in autism spectrum disorders (ASD), including tuberous sclerosis complex (TSC). The question whether inhibition or potentiation of mGluR5 could be beneficial depends, among other factors, on the specific indication. To facilitate the development of mGluR5 treatment strategies, we tested the therapeutic utility of mGluR5 negative and positive allosteric modulators (an mGluR5 NAM and PAM) for TSC, using a mutant mouse model with neuronal loss of Tsc2 that demonstrates disease-related phenotypes, including behavioral symptoms of ASD and epilepsy.

Replicable in vivo physiological and behavioral phenotypes of the null mutant mouse model of autism.

Background: Autism spectrum disorder (ASD) is a clinically and biologically heterogeneous condition characterized by social, repetitive, and sensory behavioral abnormalities. No treatments are approved for the core diagnostic symptoms of ASD. To enable the earliest stages of therapeutic discovery and development for ASD, robust and reproducible behavioral phenotypes and biological markers are essential to establish in preclinical animal models.

Translational use of event-related potentials to assess circuit integrity in ASD.

Deficits in social cognition are the defining characteristic of autism spectrum disorder (ASD). Social cognition requires the integration of several neural circuits in a time-sensitive fashion, so impairments in social interactions could arise as a result of alterations in network connectivity. Electroencephalography (EEG) has revealed abnormalities in event related potentials (ERPs) evoked by auditory and visual sensory stimuli in humans with ASD, indicating disruption of neural connectivity.

Peripheral Administration of a Long-Acting Peptide Oxytocin Receptor Agonist Inhibits Fear-Induced Freezing.

Oxytocin (OT) modulates the expression of social and emotional behaviors and consequently has been proposed as a pharmacologic treatment of psychiatric diseases, including autism spectrum disorders and schizophrenia; however, endogenous OT has a short half-life in plasma and poor permeability across the blood-brain barrier. Recent efforts have focused on the development of novel drug delivery methods to enhance brain penetration, but few efforts have aimed at improving its half-life. To explore the behavioral efficacy of an OT analog with enhanced plasma stability, we developed PF-06655075 (PF1), a novel non-brain-penetrant OT receptor agonist with increased selectivity for the OT receptor and significantly increased pharmacokinetic stability.

Oxytocin in the nucleus accumbens shell reverses CRFR2-evoked passive stress-coping after partner loss in monogamous male prairie voles.

Loss of a partner can have severe effects on mental health. Here we explore the neural mechanisms underlying increased passive stress-coping, indicative of depressive-like behavior, following the loss of the female partner in the monogamous male prairie vole. We demonstrate that corticotropin-releasing factor receptor 2 (CRFR2) in the nucleus accumbens shell mediates social loss-induced passive coping.

Melanocortin Receptor Agonists Facilitate Oxytocin-Dependent Partner Preference Formation in the Prairie Vole.

The central melanocortin (MC) system has been widely studied for its effects on food intake and sexual behavior. However, the MC system, and more specifically the MC4 receptor (MC4R), also interacts with neurochemical systems that regulate socioemotional behaviors, including oxytocin (OT) and dopamine. In monogamous prairie voles, OT and dopamine interact to promote partner preference formation, a laboratory measure of an enduring social bond between mates.

Neonatal melanocortin receptor agonist treatment reduces play fighting and promotes adult attachment in prairie voles in a sex-dependent manner.

The melanocortin receptor (MCR) system has been studied extensively for its role in feeding and sexual behavior, but effects on social behavior have received little attention. α-MSH interacts with neural systems involved in sociality, including oxytocin, dopamine, and opioid systems. Acute melanotan-II (MTII), an MC3/4R agonist, potentiates brain oxytocin (OT) release and facilitates OT-dependent partner preference formation in socially monogamous prairie voles.

Aerosolized oxytocin increases cerebrospinal fluid oxytocin in rhesus macaques.

Intranasal (IN) administration is a widely used method for examining the effect of oxytocin (OT) on social behavior and cognition in healthy subjects and psychiatric populations. IN-OT in humans enhances trust, emotional perception, and empathetic behavior and is under investigation as a potential pharmacotherapy to enhance social functioning in a variety of neuropsychiatric disorders, including autism spectrum disorders (ASD). Nonhuman primates (NHP) are an important model for understanding the effect of OT on social cognition, its neural mechanisms, and the development of IN-OT as a pharmacotherapy for treating social deficits in humans.

Advancing the discovery of medications for autism spectrum disorder using new technologies to reveal social brain circuitry in rodents.

Introduction: Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by core differences and impairments in social behavioral functioning. There are no approved medications for improving social cognition and behavior in ASD, and the underlying mechanisms needed to discover safer, more effective medications are unclear.

Discussion: In this review, we diagram the basic neurocircuitry governing social behaviors in order to provide a neurobiological framework for the origins of the core social behavioral symptoms of ASD.

Intranasal oxytocin selectively attenuates rhesus monkeys' attention to negative facial expressions.

Intranasal oxytocin (IN-OT) modulates social perception and cognition in humans and could be an effective pharmacotherapy for treating social impairments associated with neuropsychiatric disorders, like autism. However, it is unknown how IN-OT modulates social cognition, its effect after repeated use, or its impact on the developing brain. Animal models are urgently needed.

Identification of variables contributing to superovulation efficiency for production of transgenic prairie voles (Microtus ochrogaster).

Background: The prairie vole (Microtus ochrogaster) is an emerging animal model for biomedical research because of its rich sociobehavioral repertoire. Recently, lentiviral transgenic technology has been used to introduce the gene encoding the green fluorescent protein (GFP) into the prairie vole germline. However, the efficiency of transgenesis in this species is limited by the inability to reliably produce large numbers of fertilized embryos.

The oxytocin system in drug discovery for autism: animal models and novel therapeutic strategies.

Animal models and behavioral paradigms are critical for elucidating the neural mechanism involved in complex behaviors, including social cognition. Both genotype and phenotype based models have implicated the neuropeptide oxytocin (OT) in the regulation of social behavior. Based on the findings in animal models, alteration of the OT system has been hypothesized to play a role in the social deficits associated with autism and other neuropsychiatric disorders.

D-cycloserine facilitates socially reinforced learning in an animal model relevant to autism spectrum disorders.

Background: There are no drugs that specifically target the social deficits of autism spectrum disorders (ASD). This may be due to a lack of behavioral paradigms in animal models relevant to ASD. Partner preference formation in the prairie vole represents a social cognitive process involving socially reinforced learning.