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.

Effects of sulfatide on peripheral nerves in metachromatic leukodystrophy.

Objective: To evaluate the longitudinal correlations between sulfatide/lysosulfatide levels and central and peripheral nervous system function in children with metachromatic leukodystrophy (MLD) and to explore the impact of intravenous recombinant human arylsulfatase A (rhASA) treatment on myelin turnover.

Methods: A Phase 1/2 study of intravenous rhASA investigated cerebrospinal fluid (CSF) and sural nerve sulfatide levels, 88-item Gross Motor Function Measure (GMFM-88) total score, sensory and motor nerve conduction, brain N-acetylaspartate (NAA) levels, and sural nerve histology in 13 children with MLD. Myelinated and unmyelinated nerves from an untreated MLD mouse model were also analyzed.

Amiodarone for the Treatment of Arrhythmias in COVID-19 Patients Does Not Increase the Risk of Pulmonary Fibrosis: A Retrospective Cohort Study.

Amiodarone is a class III antiarrhythmic medication used to treat atrial and ventricular tachyarrhythmias. Pulmonary fibrosis from amiodarone use is a well-documented side effect. Pre-COVID-19 pandemic studies have shown that amiodarone-induced pulmonary fibrosis occurs in 1%-5% of patients and usually occurs between 12 to 60 months after initiation.

Digital endpoints for self-administered home-based functional assessment in pediatric Friedreich's ataxia.

Background: Friedreich's ataxia is an inherited, progressive, neurodegenerative disease that typically begins in childhood. Disease severity is commonly assessed with rating scales, such as the modified Friedreich's Ataxia Rating Scale, which are usually administered in the clinic by a neurology specialist.

Objective: This study evaluated the utility of home-based, self-administered digital endpoints in children with Friedreich's ataxia and unaffected controls and their relationship to standard clinical rating scales.

A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior.

DREADDs are chemogenetic tools widely used to remotely control cellular signaling, neuronal activity, and behavior. Here we used a structure-based approach to develop a new Gi-coupled DREADD using the kappa-opioid receptor as a template (KORD) that is activated by the pharmacologically inert ligand salvinorin B (SALB). Activation of virally expressed KORD in several neuronal contexts robustly attenuated neuronal activity and modified behaviors.

Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism.

The OPRM1 A118G polymorphism is the most widely studied μ-opioid receptor (MOR) variant. Although its involvement in acute alcohol effects is well characterized, less is known about the extent to which it alters responses to opioids. Prior work has shown that both electrophysiological and analgesic responses to morphine but not to fentanyl are moderated by OPRM1 A118G variation, but the mechanism behind this dissociation is not known.

A pharmacogenetic determinant of mu-opioid receptor antagonist effects on alcohol reward and consumption: evidence from humanized mice.

Background: It has been proposed that therapeutic responses to naltrexone in alcoholism are moderated by variation at the mu-opioid receptor gene locus (OPRM1). This remains controversial because human results vary and no prospectively genotyped studies have been reported. We generated humanized mice carrying the respective human OPRM1 A118G alleles.

The G protein-biased κ-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo.

The hypothesis that functionally selective G protein-coupled receptor (GPCR) agonists may have enhanced therapeutic benefits has revitalized interest for many GPCR targets. In particular, although κ-opioid receptor (KOR) agonists are analgesic with a low risk of dependence and abuse, their use is limited by a propensity to induce sedation, motor incoordination, hallucinations, and dysphoria-like states. Several laboratories have produced a body of work suggesting that G protein-biased KOR agonists might be analgesic with fewer side effects.

Different contributions of dopamine D1 and D2 receptor activity to alcohol potentiation of brain stimulation reward in C57BL/6J and DBA/2J mice.

C57BL/6J (C57) and DBA/2J (DBA) mice respond differently to drugs that affect dopamine systems, including alcohol. The current study compared effects of D1 and D2 receptor agonists and antagonists, and the interaction between D1/D2 antagonists and alcohol, on intracranial self-stimulation in male C57 and DBA mice to determine the role of dopamine receptors in the effects of alcohol on brain stimulation reward (BSR). In the initial strain comparison, dose effects on BSR thresholds and maximum operant response rates were determined for the D1 receptor agonist SKF-82958 (±-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.

Effects of the neuroactive steroid allopregnanolone on intracranial self-stimulation in C57BL/6J mice.

Rationale: The neuroactive steroid (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP, allopregnanolone) has effects on reward-related behaviors in mice and rats that suggest that it may activate brain reward circuits. Intracranial self-stimulation (ICSS) is an operant behavioral technique that detects changes in the sensitivity of brain reward circuitry following drug administration.

Objective: To examine the effects of the neuroactive steroid allopregnanolone on ICSS and to compare these effects to those of cocaine.

Levetiracetam results in increased and decreased alcohol drinking with different access procedures in C57BL/6J mice.

The antiepileptic levetiracetam (LEV) has been investigated for the treatment of alcohol abuse. However, little is known about how LEV alters the behavioral effects of alcohol in laboratory animals. The acute effects of LEV on alcohol drinking by male C57BL/6J mice were investigated using two different drinking procedures, limited access [drinking-in-the-dark (DID)] and intermittent access (IA) drinking.

Changes in sensitivity of reward and motor behavior to dopaminergic, glutamatergic, and cholinergic drugs in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is a leading cause of intellectual disability. FXS is caused by loss of function of the FMR1 gene, and mice in which Fmr1 has been inactivated have been used extensively as a preclinical model for FXS. We investigated the behavioral pharmacology of drugs acting through dopaminergic, glutamatergic, and cholinergic systems in fragile X (Fmr1 (-/Y)) mice with intracranial self-stimulation (ICSS) and locomotor activity measurements.

Levetiracetam has opposite effects on alcohol- and cocaine-related behaviors in C57BL/6J mice.

The antiepileptic drug levetiracetam (LEV) is a potential treatment for alcohol use disorders, yet few preclinical studies exist on its effects in animal models relevant to drug or alcohol abuse. We investigated the effects of LEV on locomotor stimulation following acute and repeated administration of alcohol or cocaine and on alcohol- and cocaine-mediated changes in responding for brain stimulation reward (BSR) in C57BL/6J mice. LEV alone (10.

Pathway-specific dopaminergic deficits in a mouse model of Angelman syndrome.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by maternal deletions or mutations of the ubiquitin ligase E3A (UBE3A) allele and characterized by minimal verbal communication, seizures, and disorders of voluntary movement. Previous studies have suggested that abnormal dopamine neurotransmission may underlie some of these deficits, but no effective treatment currently exists for the core features of AS. A clinical trial of levodopa (L-DOPA) in AS is ongoing, although the underlying rationale for this treatment strategy has not yet been thoroughly examined in preclinical models.

Mephedrone (4-methylmethcathinone) and intracranial self-stimulation in C57BL/6J mice: comparison to cocaine.

The recreational use of cathinone-derived synthetic stimulants, also known as "bath salts", has increased during the last five years. A commonly abused drug in this class is mephedrone (4-methylmethcathinone or "meow-meow"), which alters mood and produces euphoria in humans. Intracranial self-stimulation (ICSS) measures the behavioral effects of neuroactive compounds on brain reward circuitry.

The rewarding and locomotor-sensitizing effects of repeated cocaine administration are distinct and separable in mice.

Repeated psychostimulant exposure progressively increases their potency to stimulate motor activity in rodents. This behavioral or locomotor sensitization is considered a model for some aspects of drug addiction in humans, particularly drug craving during abstinence. However, the role of increased motor behavior in drug reward remains incompletely understood.

Orexin-1 receptor antagonism does not reduce the rewarding potency of cocaine in Swiss-Webster mice.

The orexin family of hypothalamic neuropeptides has been implicated in reinforcement mechanisms relevant to both food and drug reward. Previous behavioral studies with antagonists at the orexin A-selective receptor, OX(1), have demonstrated its involvement in behavioral sensitization, conditioned place-preference, and self-administration of drugs of abuse. Adult male Swiss-Webster mice were implanted with stimulating electrodes to the lateral hypothalamus and trained to perform intracranial self-stimulation (ICSS).

Intracranial self-stimulation in FAST and SLOW mice: effects of alcohol and cocaine.

Rationale: Sensitivity to the stimulant and rewarding effects of alcohol may be genetically correlated traits that predispose individuals to develop an alcohol use disorder.

Objective: This study aimed to examine the effects of alcohol and cocaine on intracranial self-stimulation (ICSS) in FAST and SLOW mice, which were selectively bred for extremes in alcohol stimulation.

Methods: Male FAST and SLOW mice were conditioned to respond for reinforcement by direct electrical stimulation of the medial forebrain bundle (i.

Potentiation of brain stimulation reward by morphine: effects of neurokinin-1 receptor antagonism.

Rationale: The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists.

Objective: This study was conducted to measure the effects of opioid and NK1R blockade on the potentiation of brain stimulation reward (BSR) by morphine using the intracranial self-stimulation method.

Methods: Adult male C57BL/6J mice (n = 15) were implanted with unipolar stimulating electrodes in the lateral hypothalamus and trained to respond for varying frequencies of rewarding electrical stimulation.

Definition and classification of hyperkinetic movements in childhood.

Hyperkinetic movements are unwanted or excess movements that are frequently seen in children with neurologic disorders. They are an important clinical finding with significant implications for diagnosis and treatment. However, the lack of agreement on standard terminology and definitions interferes with clinical treatment and research.

Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation.

Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes.

Alcohol, cocaine, and brain stimulation-reward in C57Bl6/J and DBA2/J mice.

Background: Pleasure and reward are critical features of alcohol drinking that are difficult to measure in animal studies. Intracranial self-stimulation (ICSS) is a behavioral method for studying the effects of drugs directly on the neural circuitry that underlies brain reward. These experiments had 2 objectives: first, to establish the effects of alcohol on ICSS responding in the C57Bl6/J (C57) and DBA2/J (DBA) mouse strains; and second, to compare these effects to those of the psychostimulant cocaine.

From the SmA to the hexatic, including the SmC*, SmC*(A) and SmC*(re) phases: a 2H NMR relaxation study.

The molecular dynamics of a ferroelectric liquid crystal, denoted ZLL 7/*, is investigated by means of (2)H NMR relaxation. The spin-lattice (T(1Q) and T(1Z)) and spin-spin (T(2)) relaxation times of two isotopomers of ZLL 7/*, labeled on the phenyl and biphenyl fragments, are measured and their behavior upon passing from the SmA to the hexatic phase, through the ferroelectric SmC*, antiferroelectric SmC*(A), and re-entrant ferroelectric SmC*(re) phases, is discussed. A comparison between the measured T(2) and T(2)*, directly related to the experimental linewidth, provides information on the heterogeneity of the system, thus allowing confirmation of previous hypotheses concerning the structural and ordering properties of the SmC*(A) and SmC*(re) phases.