Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers. METHODS: A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration. RESULTS: A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing. DISCUSSION: Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials.

Prediction of the Liver Safety Profile of a First-in-Class Myeloperoxidase Inhibitor Using Quantitative Systems Toxicology Modeling.

The novel myeloperoxidase inhibitor verdiperstat was developed as a treatment for neuroinflammatory and neurodegenerative diseases. During development, a computational prediction of verdiperstat liver safety was performed using DILIsym v8A, a quantitative systems toxicology (QST) model of liver safety.A physiologically-based pharmacokinetic (PBPK) model of verdiperstat was constructed in GastroPlus 9.8, and outputs for liver and plasma time courses of verdiperstat were input into DILIsym. In vitro experiments measured the likelihood that verdiperstat would inhibit mitochondrial function, inhibit bile acid transporters, and generate reactive oxygen species (ROS); these results were used as inputs into DILIsym, with two alternate sets of parameters used in order to fully explore the sensitivity of model predictions. Verdiperstat dosing protocols up to 600 mg BID were simulated for up to 48 weeks using a simulated population (SimPops) in DILIsym.Verdiperstat was predicted to be safe, with only very rare, mild liver enzyme increases as a potential possibility in highly sensitive individuals. Subsequent Phase 3 clinical trials found that ALT elevations in the verdiperstat treatment group were generally similar to those in the placebo group. This validates the DILIsym simulation results and demonstrates the power of QST modeling to predict the liver safety profile of novel therapeutics.

Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease.

Novel classes of small and long non-coding RNAs (ncRNAs) are being characterized at a rapid pace, driven by recent paradigm shifts in our understanding of genomic architecture, regulation and transcriptional output, as well as by innovations in sequencing technologies and computational and systems biology. These ncRNAs can interact with DNA, RNA and protein molecules; engage in diverse structural, functional and regulatory activities; and have roles in nuclear organization and transcriptional, post-transcriptional and epigenetic processes. This expanding inventory of ncRNAs is implicated in mediating a broad spectrum of processes including brain evolution, development, synaptic plasticity and disease pathogenesis.

Sex, epilepsy, and epigenetics.

Epilepsy refers to a heterogeneous group of disorders that are associated with a wide range of pathogenic mechanisms, seizure manifestations, comorbidity profiles, and therapeutic responses. These characteristics are all influenced quite significantly by sex. As with other conditions exhibiting such patterns, sex differences in epilepsy are thought to arise-at the most fundamental level-from the "organizational" and "activational" effects of sex hormones as well as from the direct actions of the sex chromosomes. However, our understanding of the specific molecular, cellular, and network level processes responsible for mediating sex differences in epilepsy remains limited. Because increasing evidence suggests that epigenetic mechanisms are involved both in epilepsy and in brain sexual dimorphism, we make the case here that analyzing epigenetic regulation will provide novel insights into the basis for sex differences in epilepsy.

Epigenetics of sleep and chronobiology.

The circadian clock choreographs fundamental biological rhythms. This system is comprised of the master circadian pacemaker in the suprachiasmatic nucleus and associated pacemakers in other tissues that coordinate complex physiological processes and behaviors, such as sleep, feeding, and metabolism. The molecular circuitry that underlies these clocks and orchestrates circadian gene expression has been the focus of intensive investigation, and it is becoming clear that epigenetic factors are highly integrated into these networks. In this review, we draw attention to the fundamental roles played by epigenetic mechanisms in transcriptional and post-transcriptional regulation within the circadian clock system. We also highlight how alterations in epigenetic factors and mechanisms are being linked with sleep-wake disorders. These observations provide important insights into the pathogenesis and potential treatment of these disorders and implicate epigenetic deregulation in the significant but poorly understood interconnections now emerging between circadian processes and neurodegeneration, metabolic diseases, cancer, and aging.

Targeting myeloperoxidase to reduce neuroinflammation in X-linked dystonia parkinsonism.

Although the genetic locus of X-linked dystonia parkinsonism (XDP), a neurodegenerative disease endemic in the Philippines, is well-characterized, the exact molecular mechanisms leading to neuronal loss are not yet fully understood. Recently, we demonstrated a significant increase in astrogliosis and microgliosis together with an increase in myeloperoxidase (MPO) levels in XDP post-mortem prefrontal cortex (PFC), suggesting a role for neuroinflammation in XDP pathogenesis. Here, we demonstrated a significant increase in MPO activity in XDP PFC using a novel specific MPO-activatable fluorescent agent (MAFA). Additionally, we demonstrated a significant increase in reactive oxygen species (ROS) in XDP-derived fibroblasts as well as in SH-SY5Y cells treated with post-mortem XDP PFC, further supporting a role for MPO in XDP. To determine whether increases in MPO activity were linked to increases in ROS, MPO content was immuno-depleted from XDP PFC [MPO(-)], which resulted in a significant decrease in ROS in SH-SY5Y cells. Consistently, the treatment with verdiperstat, a potent and selective MPO inhibitor, significantly decreased ROS in both XDP-derived fibroblasts and XDP PFC-treated SH-SY5Y cells. Collectively, our results suggest that MPO inhibition mitigates oxidative stress and may provide a novel therapeutic strategy for XDP treatment. Highlights: MPO activity is increased in XDP post-mortem prefrontal cortex.MPO activity is increased in cellular models of XDP.MPO increases reactive oxygen species (ROS) in vitro.Inhibiting MPO mitigates ROS in XDP.The MPO inhibitor, verdiperstat, dampens ROS suggesting a potential therapeutic strategy for XDP.

Corepressor for element-1-silencing transcription factor preferentially mediates gene networks underlying neural stem cell fate decisions.

The repressor element-1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) silences neuronal genes in neural stem cells (NSCs) and nonneuronal cells through its role as a dynamic modular platform for recruitment of transcriptional and epigenetic regulatory cofactors to RE1-containing promoters. In embryonic stem cells, the REST regulatory network is highly integrated with the transcriptional circuitry governing self-renewal and pluripotency, although its exact functional role is unclear. The C-terminal cofactor for REST, CoREST, also acts as a modular scaffold, but its cell type-specific roles have not been elucidated. We used chromatin immunoprecipitation-on-chip to examine CoREST and REST binding sites in NSCs and their proximate progenitor species. In NSCs, we identified a larger number of CoREST (1,820) compared with REST (322) target genes. The majority of these CoREST targets do not contain known RE1 motifs. Notably, these CoREST target genes do play important roles in pluripotency networks, in modulating NSC identity and fate decisions and in epigenetic processes previously associated with both REST and CoREST. Moreover, we found that NSC-mediated developmental transitions were associated primarily with liberation of CoREST from promoters with transcriptional repression favored in less lineage-restricted radial glia and transcriptional activation favored in more lineage-restricted neuronal-oligodendrocyte precursors. Clonal NSC REST and CoREST gene manipulation paradigms further revealed that CoREST has largely independent and previously uncharacterized roles in promoting NSC multilineage potential and modulating early neural fate decisions.

T2 Protect AD: Achieving a rapid recruitment timeline in a multisite clinical trial for individuals with mild to moderate Alzheimer's disease.

Introduction: The reporting of approaches facilitating the most efficient and timely recruitment of Alzheimer's disease (AD) patients into pharmacologic trials is fundamental to much-needed therapeutic progress. Methods: T2 Protect AD (T2), a phase 2 randomized placebo-controlled trial of troriluzole in mild to moderate AD, used multiple recruitment strategies. Results: T2 exceeded its recruitment target, enrolling 350 participants between July 2018 and December 2019 (randomization rate: 0.87 randomizations/site/month, or 3-fold greater than recent trials of mild to moderate AD). The vast majority (98%) of participants were enrolled during a 10-month window of intense promotion in news media, TV and radio advertisements, and social media. The distribution of primary recruitment sources included: existing patient lists at participating sites (72.3%), news media (12.3%), physician referral (6.0%), word of mouth (3.1%), and paid advertising (2.9%). Discussion: The rapid recruitment of participants with mild to moderate AD was achieved through a range of approaches with varying success.

Advances in epigenetics and epigenomics for neurodegenerative diseases.

In the post-genomic era, epigenetic factors-literally those that are "over" or "above" genetic ones and responsible for controlling the expression and function of genes-have emerged as important mediators of development and aging; gene-gene and gene-environmental interactions; and the pathophysiology of complex disease states. Here, we provide a brief overview of the major epigenetic mechanisms (ie, DNA methylation, histone modifications and chromatin remodeling, and non-coding RNA regulation). We highlight the nearly ubiquitous profiles of epigenetic dysregulation that have been found in Alzheimer's and other neurodegenerative diseases. We also review innovative methods and technologies that enable the characterization of individual epigenetic modifications and more widespread epigenomic states at high resolution. We conclude that, together with complementary genetic, genomic, and related approaches, interrogating epigenetic and epigenomic profiles in neurodegenerative diseases represent important and increasingly practical strategies for advancing our understanding of and the diagnosis and treatment of these disorders.

Epigenetic mechanisms underlying human epileptic disorders and the process of epileptogenesis.

The rapidly emerging science of epigenetics and epigenomic medicine promises to reveal novel insights into the susceptibility to and the onset and progression of epileptic disorders. Epigenetic regulatory mechanisms are now implicated in orchestrating aspects of neural development (e.g., cell fate specification and maturation), homeostasis and stress responses (e.g., immediate early gene transcription), and neural network function (e.g., excitation-inhibition coupling and activity-dependent plasticity). These same neurobiological processes are responsible for determining the heterogeneous features of complex epileptic disease states. Thus, we highlight recent evidence that is beginning to elucidate the specific roles played by epigenetic mechanisms, including DNA methylation, histone code modifications and chromatin remodeling, noncoding RNAs and RNA editing, in human epilepsy syndromes and in the process of epileptogenesis. The highly integrated layers of the epigenome are responsible for the cell type specific and exquisitely environmentally responsive deployment of genes and functional gene networks that underlie the molecular pathophysiology of epilepsy and its associated comorbidities, including but not limited to neurotransmitter receptors (e.g., GluR2, GLRA2, and GLRA3), growth factors (e.g., BDNF), extracellular matrix proteins (e.g., RELN), and diverse transcriptional regulators (e.g., CREB, c-fos, and c-jun). These important observations suggest that future epigenetic studies are necessary to better understand, classify, prevent, and treat epileptic disorders.

Long noncoding RNAs in neuronal-glial fate specification and oligodendrocyte lineage maturation.

BACKGROUND: Long non-protein-coding RNAs (ncRNAs) are emerging as important regulators of cellular differentiation and are widely expressed in the brain. RESULTS: Here we show that many long ncRNAs exhibit dynamic expression patterns during neuronal and oligodendrocyte (OL) lineage specification, neuronal-glial fate transitions, and progressive stages of OL lineage elaboration including myelination. Consideration of the genomic context of these dynamically regulated ncRNAs showed they were part of complex transcriptional loci that encompass key neural developmental protein-coding genes, with which they exhibit concordant expression profiles as indicated by both microarray and in situ hybridization analyses. These included ncRNAs associated with differentiation-specific nuclear subdomains such as Gomafu and Neat1, and ncRNAs associated with developmental enhancers and genes encoding important transcription factors and homeotic proteins. We also observed changes in ncRNA expression profiles in response to treatment with trichostatin A, a histone deacetylase inhibitor that prevents the progression of OL progenitors into post-mitotic OLs by altering lineage-specific gene expression programs. CONCLUSION: This is the first report of long ncRNA expression in neuronal and glial cell differentiation and of the modulation of ncRNA expression by modification of chromatin architecture. These observations explicitly link ncRNA dynamics to neural stem cell fate decisions, specification and epigenetic reprogramming and may have important implications for understanding and treating neuropsychiatric diseases.

Assessing Effects of BHV-0223 40 mg Zydis Sublingual Formulation and Riluzole 50 mg Oral Tablet on Liver Function Test Parameters Utilizing DILIsym.

For patients with amyotrophic lateral sclerosis who take oral riluzole tablets, approximately 50% experience alanine transaminase (ALT) levels above upper limit of normal (ULN), 8% above 3× ULN, and 2% above 5× ULN. BHV-0223 is a novel 40 mg rapidly sublingually disintegrating (Zydis) formulation of riluzole, bioequivalent to conventional riluzole 50 mg oral tablets, that averts the need for swallowing tablets and mitigates first-pass hepatic metabolism, thereby potentially reducing risk of liver toxicity. DILIsym is a validated multiscale computational model that supports evaluation of liver toxicity risks. DILIsym was used to compare the hepatotoxicity potential of oral riluzole tablets (50 mg BID) versus BHV-0223 (40 mg BID) by integrating clinical data and in vitro toxicity data. In a simulated population (SimPops), ALT levels > 3× ULN were predicted in 3.9% (11/285) versus 1.4% (4/285) of individuals with oral riluzole tablets and sublingual BHV-0223, respectively. This represents a relative risk reduction of 64% associated with BHV-0223 versus conventional riluzole tablets. Mechanistic investigations revealed that oxidative stress was responsible for the predicted ALT elevations. The validity of the DILIsym representation of riluzole and assumptions is supported by its ability to predict rates of ALT elevations for riluzole oral tablets comparable with that observed in clinical data. Combining a mechanistic, quantitative representation of hepatotoxicity with interindividual variability in both susceptibility and liver exposure suggests that sublingual BHV-0223 confers diminished rates of liver toxicity compared with oral tablets of riluzole, consistent with having a lower overall dose of riluzole and bypassing first-pass liver metabolism.

Predicting Amyloid-ß Levels in Amnestic Mild Cognitive Impairment Using Machine Learning Techniques.

BACKGROUND: Amyloid-ß positivity (Aß+) based on PET imaging is part of the enrollment criteria for many of the clinical trials of Alzheimer's disease (AD), particularly in trials for amyloid-targeted therapy. Predicting Aß positivity prior to PET imaging can decrease unnecessary patient burden and costs of running these trials. OBJECTIVE: The aim of this study was to evaluate the performance of a machine learning model in estimating the individual risk of Aß+ based on gold-standard of PET imaging. METHODS: We used data from an amnestic mild cognitive impairment (aMCI) subset of the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort to develop and validate the models. The predictors of Aß status included demographic and ApoE4 status in all models plus a combination of neuropsychological tests (NP), MRI volumetrics, and cerebrospinal fluid (CSF) biomarkers. RESULTS: The models that included NP and MRI measures separately showed an area under the receiver operating characteristics (AUC) of 0.74 and 0.72, respectively. However, using NP and MRI measures jointly in the model did not improve prediction. The models including CSF biomarkers significantly outperformed other models with AUCs between 0.89 to 0.92. CONCLUSIONS: Predictive models can be effectively used to identify persons with aMCI likely to be amyloid positive on a subsequent PET scan.

Epigenetic mechanisms underlying nervous system diseases.

Epigenetic mechanisms act as control systems for modulating genomic structure and activity in response to evolving profiles of cell-extrinsic, cell-cell, and cell-intrinsic signals. These dynamic processes are responsible for mediating cell- and tissue-specific gene expression and function and gene-gene and gene-environmental interactions. The major epigenetic mechanisms include DNA methylation and hydroxymethylation; histone protein posttranslational modifications, nucleosome remodeling/repositioning, and higher-order chromatin reorganization; noncoding RNA regulation; and RNA editing. These mechanisms are intimately involved in executing fundamental genomic programs, including gene transcription, posttranscriptional RNA processing and transport, translation, X-chromosome inactivation, genomic imprinting, retrotransposon regulation, DNA replication, and DNA repair and the maintenance of genomic stability. For the nervous system, epigenetics offers a novel and robust framework for explaining how brain development and aging occur, neural cellular diversity is generated, synaptic and neural network connectivity and plasticity are mediated, and complex cognitive and behavioral phenotypes are inherited transgenerationally. Epigenetic factors and processes are, not surprisingly, implicated in nervous system disease pathophysiology through several emerging paradigms - mutations and genetic variation in genes encoding epigenetic factors; impairments in epigenetic factor expression, localization, and function; epigenetic mechanisms modulating disease-associated factors and pathways; and the presence of deregulated epigenetic profiles in central and peripheral tissues.

A randomized, single ascending dose study of intravenous BIIB092 in healthy participants.

INTRODUCTION: Extracellular tau is hypothesized to mediate the onset and progression of tauopathies, including Alzheimer's disease, progressive supranuclear palsy, and a subset of frontotemporal lobar degenerations. A putative strategy for treating these disorders is to reduce extracellular tau levels using tau-directed immunotherapy. The results of the first-in-human study of BIIB092 (formerly BMS-986168/IPN007), a humanized monoclonal antibody that binds to N-terminal tau, are reported here. This randomized, double-blind, single ascending dose study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity profile of BIIB092 after a single intravenous infusion in healthy participants. METHODS: Sixty-five participants were randomized to receive a single intravenous infusion of placebo or BIIB092 at doses of 21, 70, 210, 700, 2100, or 4200 mg (or 700 or 2100 mg for Japanese participants). Serial blood and cerebrospinal fluid samples were obtained for assessment of pharmacokinetic parameters and unbound N-terminal tau suppression. RESULTS: There were no deaths, serious adverse events (AEs), severe AEs, or discontinuations due to an AE. The majority of AEs were mild. Serum BIIB092 concentrations increased in a dose-proportional manner and suppressed unbound cerebrospinal fluid N-terminal tau by 67%-97% at 28 days after dose, with doses of ≥210 mg producing persistent unbound N-terminal tau suppression over 12 weeks. Levels of cerebrospinal fluid N-terminal tau suppression were similar for Japanese and non-Japanese participants. DISCUSSION: BIIB092 was generally safe and well tolerated after a single dose of up to 4200 mg, and up to 2100 mg in Japanese participants. BIIB092 exhibited a dose-dependent increase in the extent and duration of unbound N-terminal tau suppression.

Epigenetics and therapeutic targets mediating neuroprotection.

The rapidly evolving science of epigenetics is transforming our understanding of the nervous system in health and disease and holds great promise for the development of novel diagnostic and therapeutic approaches targeting neurological diseases. Increasing evidence suggests that epigenetic factors and mechanisms serve as important mediators of the pathogenic processes that lead to irrevocable neural injury and of countervailing homeostatic and regenerative responses. Epigenetics is, therefore, of considerable translational significance to the field of neuroprotection. In this brief review, we provide an overview of epigenetic mechanisms and highlight the emerging roles played by epigenetic processes in neural cell dysfunction and death and in resultant neuroprotective responses. This article is part of a Special Issue entitled SI: Neuroprotection.

Epigenetic mechanisms underlying the pathogenesis of neurogenetic diseases.

There have been considerable advances in uncovering the complex genetic mechanisms that underlie nervous system disease pathogenesis, particularly with the advent of exome and whole genome sequencing techniques. The emerging field of epigenetics is also providing further insights into these mechanisms. Here, we discuss our understanding of the interplay that exists between genetic and epigenetic mechanisms in these disorders, highlighting the nascent field of epigenetic epidemiology-which focuses on analyzing relationships between the epigenome and environmental exposures, development and aging, other health-related phenotypes, and disease states-and next-generation research tools (i.e., those leveraging synthetic and chemical biology and optogenetics) for examining precisely how epigenetic modifications at specific genomic sites affect disease processes.

An evolving view of epigenetic complexity in the brain.

Recent scientific advances have revolutionized our understanding of classical epigenetic mechanisms and the broader landscape of molecular interactions and cellular functions that are inextricably linked to these processes. Our current view of epigenetics includes an increasing appreciation for the dynamic nature of DNA methylation, active mechanisms for DNA demethylation, differential functions of 5-methylcytosine and its oxidized derivatives, the intricate regulatory logic of histone post-translational modifications, the incorporation of histone variants into chromatin, nucleosome occupancy and dynamics, and direct links between cellular signalling pathways and the actions of chromatin 'reader', 'writer' and 'eraser' molecules. We also have an increasing awareness of the seemingly ubiquitous roles played by diverse classes of selectively expressed non-coding RNAs in transcriptional, post-transcriptional, post-translational and local and higher order chromatin modulatory processes. These perspectives are still evolving with novel insights continuing to emerge rapidly (e.g. those related to epigenetic regulation of mobile genetic elements, epigenetic mechanisms in mitochondria, roles in nuclear architecture and 'RNA epigenetics'). The precise functions of these epigenetic factors/phenomena are largely unknown. However, it is unequivocal that they serve as key mediators of brain complexity and flexibility, including neural development and aging, cellular differentiation, homeostasis, stress responses, and synaptic and neural network connectivity and plasticity.

Epigenetic mechanisms governing the process of neurodegeneration.

Studies elucidating how and why neurodegeneration unfolds suggest that a complex interplay between genetic and environmental factors is responsible for disease pathogenesis. Recent breakthroughs in the field of epigenetics promise to advance our understanding of these mechanisms and to promote the development of useful and effective pre-clinical risk stratification strategies, molecular diagnostic and prognostic methods, and disease-modifying treatments.