Long-term treatment with ganaxolone for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: Two-year open-label extension follow-up.

Objective: In the placebo-controlled, double-blind phase of the Marigold study (NCT03572933), ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with cyclin-dependent kinase-like 5 deficiency disorder (CDD). We report 2-year safety and clinical outcomes data from the open-label extension (OLE) phase of Marigold.

Methods: Patients with CDD who completed the double-blind phase were eligible to continue in the OLE.

Phase 2, placebo-controlled clinical study of oral ganaxolone in PCDH19-clustering epilepsy.

Introduction: Protocadherin-19 (PCDH19)-clustering epilepsy is a distinct developmental and epileptic encephalopathy characterized by early-onset seizures that are often treatment refractory. Caused by a mutation of the PCDH19 gene on the X chromosome, this rare epilepsy syndrome primarily affects females with seizure onset commonly in the first year of life. A global, randomized, double-blind, placebo-controlled, phase 2 trial was conducted to evaluate the efficacy, safety, and tolerability of ganaxolone compared with placebo as adjunctive therapy to a standard antiseizure medication regimen in patients with PCDH19-clustering epilepsy (VIOLET; NCT03865732).

Intravenous ganaxolone for the treatment of refractory status epilepticus: Results from an open-label, dose-finding, phase 2 trial.

Objective: Patients with refractory status epilepticus (RSE) have failed treatment with benzodiazepines and ≥1 second-line intravenous (IV) antiseizure medication (ASM). Guidelines recommend IV anesthesia when second-line ASMs have failed, but potential harms can outweigh the benefits. Novel treatments are needed to stop and durably control RSE without escalation to IV anesthetics.

Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial.

Background: CDKL5 deficiency disorder (CDD) is a rare, X-linked, developmental and epileptic encephalopathy characterised by severe global developmental impairment and seizures that can begin in the first few months after birth and are often treatment refractory. Ganaxolone, an investigational neuroactive steroid, reduced seizure frequency in an open-label, phase 2 trial that included patients with CDD. We aimed to further assess the efficacy and safety of ganaxolone in patients with CDD-associated refractory epilepsy.

Association Between Treatment Progression, Disease Refractoriness, and Burden of Illness Among Hospitalized Patients With Status Epilepticus.

Importance: Status epilepticus (SE) is associated with poor clinical outcomes and high cost. Increased levels of refractory SE require treatment with additional medications and carry increased morbidity and mortality, but the associations between SE refractoriness, clinical outcomes, and cost remain poorly characterized.

Objective: To examine differences in clinical outcomes and costs associated with hospitalization for SE of varying refractoriness.

Natural history of neurological improvement following complete (AIS A) thoracic spinal cord injury across three registries to guide acute clinical trial design and interpretation.

Study Design: Retrospective, longitudinal analysis of motor and sensory outcomes following thoracic (T2-T12) sensorimotor complete spinal cord injury (SCI) in selected patients enrolled into three SCI) registries.

Objectives: To establish a modern-day international benchmark for neurological recovery following traumatic complete thoracic sensorimotor SCI in a population similar to those enrolled in acute clinical trials.

Setting: Affiliates of the North American Clinical Trial Network (NACTN), European Multicenter Study about Spinal Cord Injury (EMSCI), and the Spinal Cord Injury Model Systems (SCIMS).

Internal decompression of the acutely contused spinal cord: Differential effects of irrigation only versus biodegradable scaffold implantation.

Severe spinal cord injury leads to hemorrhage, edema and elevated tissue pressures that propagate ischemia. Liquefactive necrosis of damaged tissue eventually results in chronic cavities due to a wound healing process lacking adhesive contractile cells. Biomaterials can potently influence wound healing responses.

Method and Apparatus for the Automated Delivery of Continuous Neural Stem Cell Trails Into the Spinal Cord of Small and Large Animals.

Background: Immature neurons can extend processes after transplantation in adult animals. Neuronal relays can form between injected neural stem cells (NSCs) and surviving neurons, possibly improving recovery after spinal cord injury (SCI). Cell delivery methods of single or multiple bolus injections of concentrated cell suspensions thus far tested in preclinical and clinical experiments are suboptimal for new tract formation.

Relationship of American Spinal Injury Association Impairment Scale Grade to Post-injury Hospitalization and Costs in Thoracic Spinal Cord Injury.

Background: The lifetime economic burden of thoracic spinal cord injury (SCI) is known to be high, but evidence of variability of costs in relation to the American Spinal Injury Association Impairment Scale (AIS) grade is limited.

Objective: To estimate lifetime economic costs of hospitalization by AIS grade in thoracic SCI.

Methods: Using SCI Model Systems data from January 2000 to March 2016 from the National Spinal Cord Injury Statistical Center, we estimated mean total annual days of all-cause hospitalization by AIS grade among persons with thoracic SCI, based on assessments 1, 5, and 10 yr post-injury.

Sustained Local Release of Methylprednisolone From a Thiol-Acrylate Poly(Ethylene Glycol) Hydrogel for Treating Chronic Compressive Radicular Pain.

Study Design: A preclinical animal model of chronic ligation of the sciatic nerve was used to compare the effectiveness of a slow-release hydrogel carrying methylprednisolone to methylprednisolone injection alone, which simulates the current standard of care for chronic compressive radiculopathy (CR).

Objective: To extend the short-term benefits of steroid injections by using a nonswelling, biodegradable hydrogel as carrier to locally release methylprednisolone in a regulated and sustained way at the site of nerve compression.

Summary Of Background Data: CR affects millions worldwide annually, and is a cause of costly disability with significant societal impact.

Covalent Incorporation of Trehalose within Hydrogels for Enhanced Long-Term Functional Stability and Controlled Release of Biomacromolecules.

Hydrogels with covalently incorporated trehalose are synthesized using thiol-ene Michael addition. Trehalose hydrogels afford prolonged stabilization and -controlled release of model enzymes in vitro and in vivo as well as preservation of protein stability under heat and -lyophilization stressors. Strong and -ordered hydrogen bonding interactions within covalently incorporated trehalose hydrogels represent a possible mechanism for protein stabilization.

Synthesis and characterization of a library of in-situ curing, nonswelling ethoxylated polyol thiol-ene hydrogels for tailorable macromolecule delivery.

A transesterfication reaction is used to synthesize tri-thiol-functionalized-ethoxylated polyols that are combined with polyethylene glycol diacrylates to form a biodegradable hydrogel library. Hydrogels display nonswelling equilibration and offer temporal control over material degradation and the release of biomolecules. The demonstrated in vitro biocompatibility makes this a versatile platform that can be used for local drug delivery to volume-constrained anatomical sites.

Injectable nano-network for glucose-mediated insulin delivery.

Diabetes mellitus, a disorder of glucose regulation, is a global burden affecting 366 million people across the world. An artificial "closed-loop" system able to mimic pancreas activity and release insulin in response to glucose level changes has the potential to improve patient compliance and health. Herein we develop a glucose-mediated release strategy for the self-regulated delivery of insulin using an injectable and acid-degradable polymeric network.

Synthesis of cyclic, multivalent Arg-Gly-Asp using sequential thiol-ene/thiol-yne photoreactions.

A unique method has been developed for the formation of multivalent cyclic peptides. This procedure exploits on-resin peptide cyclization using a photoinitiated thiol-ene click reaction and subsequent clustering using thiol-yne photochemistry. Both reactions utilize the sulfhydryl group on natural cysteine amino acids to participate in the thiol-mediated reactions.

On-resin peptide macrocyclization using thiol-ene click chemistry.

A versatile and rapid synthetic strategy has been developed for the on-resin cyclization of peptides using thiol-ene photochemistry. This unique method exploits the thiol group of natural cysteine amino acids and allows for various alkenes to be incorporated orthogonal to the peptide backbone.

Regulating MCP-1 diffusion in affinity hydrogels for enhancing immuno-isolation.

Delivering cells using semi-permeable hydrogels is becoming an increasingly important direction in cell based therapies and regenerative medicine applications. Synthetic hydrogels have been functionalized with bioactive motifs to render otherwise inert polymer networks responsive. However, little effort has been focused on creating immuno-isolating materials capable of retarding the transport of small antigenic molecules secreted from the cells delivered with the synthetic carriers.

Poly(ethylene glycol) hydrogels formed by thiol-ene photopolymerization for enzyme-responsive protein delivery.

Degradable hydrogels have been extensively used in biomedical applications such as drug delivery, and recent interest has grown in hydrogels that degrade in recognition of a cellular response. This contribution describes a poly(ethylene glycol) (PEG) hydrogel platform with human neutrophil elastase (HNE) sensitive peptide cross-links formed using thiol-ene photopolymerization rendering the gel degradable at sites of inflammation. Further, protein therapeutics can be physically entrapped within the network and selectively released upon exposure to HNE.

Human neutrophil elastase responsive delivery from poly(ethylene glycol) hydrogels.

A novel enzyme-responsive hydrogel drug delivery system was developed with the potential to treat inflammation locally. Human neutrophil elastase (HNE) is a serine protease secreted by neutrophils which are the first cells recruited to inflammatory sites. We exploited this cell-secreted enzyme as a biological cue for controlled release.