scholarly journals Epilepsy Benchmarks Area III: Improved Treatment Options for Controlling Seizures and Epilepsy-Related Conditions Without Side Effects

2020 ◽  
Vol 20 (1_suppl) ◽  
pp. 23S-30S ◽  
Author(s):  
Stephen F. Traynelis ◽  
Dennis Dlugos ◽  
David Henshall ◽  
Heather C. Mefford ◽  
Michael A. Rogawski ◽  
...  
Keyword(s):  
Animal Models ◽  
Single Gene ◽  
Treatment Options ◽  
Therapeutic Strategies ◽  
Machine Learning Algorithms ◽  
High Rate ◽  
New Approaches ◽  
Human Epilepsy ◽  
Induced Pluripotent ◽  
New Treatments

The goals of Epilepsy Benchmark Area III involve identifying areas that are ripe for progress in terms of controlling seizures and patient symptoms in light of the most recent advances in both basic and clinical research. These goals were developed with an emphasis on potential new therapeutic strategies that will reduce seizure burden and improve quality of life for patients with epilepsy. In particular, we continue to support the proposition that a better understanding of how seizures are initiated, propagated, and terminated in different forms of epilepsy is central to enabling new approaches to treatment, including pharmacological as well as surgical and device-oriented approaches. The stubbornly high rate of treatment-resistant epilepsy—one-third of patients—emphasizes the urgent need for new therapeutic strategies, including pharmacological, procedural, device linked, and genetic. The development of new approaches can be advanced by better animal models of seizure initiation that represent salient features of human epilepsy, as well as humanized models such as induced pluripotent stem cells and organoids. The rapid advances in genetic understanding of a subset of epilepsies provide a path to new and direct patient-relevant cellular and animal models, which could catalyze conceptualization of new treatments that may be broadly applicable across multiple forms of epilepsies beyond those arising from variation in a single gene. Remarkable advances in machine learning algorithms and miniaturization of devices and increases in computational power together provide an enhanced opportunity to detect and mitigate seizures in real time via devices that interrupt electrical activity directly or administer effective pharmaceuticals. Each of these potential areas for advance will be discussed in turn.

scholarly journals Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jan Philipp Delling ◽  
Tobias M. Boeckers
Keyword(s):  
Animal Models ◽  
Treatment Options ◽  
Regulation Of Gene Expression ◽  
Treatment Strategies ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Therapeutic Strategies ◽  
Clinical Severity ◽  
Comprehensive Overview ◽  
Increased Risk

Abstract Background Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. Main text This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. Conclusions Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors.

Inflammational Animal Models for Schizophrenia

2015 ◽  
Vol 223 (3) ◽  
pp. 157-164 ◽  
Author(s):  
Georg Juckel
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Immune Activation ◽  
Microglial Activation ◽  
Treatment Options ◽  
Early Adulthood ◽  
Brain Regions ◽  
Synaptic Connections ◽  
Preventive Interventions ◽  
Immunological System

Abstract. Inflammational-immunological processes within the pathophysiology of schizophrenia seem to play an important role. Early signals of neurobiological changes in the embryonal phase of brain in later patients with schizophrenia might lead to activation of the immunological system, for example, of cytokines and microglial cells. Microglia then induces – via the neurotoxic activities of these cells as an overreaction – a rarification of synaptic connections in frontal and temporal brain regions, that is, reduction of the neuropil. Promising inflammational animal models for schizophrenia with high validity can be used today to mimic behavioral as well as neurobiological findings in patients, for example, the well-known neurochemical alterations of dopaminergic, glutamatergic, serotonergic, and other neurotransmitter systems. Also the microglial activation can be modeled well within one of this models, that is, the inflammational PolyI:C animal model of schizophrenia, showing a time peak in late adolescence/early adulthood. The exact mechanism, by which activated microglia cells then triggers further neurodegeneration, must now be investigated in broader detail. Thus, these animal models can be used to understand the pathophysiology of schizophrenia better especially concerning the interaction of immune activation, inflammation, and neurodegeneration. This could also lead to the development of anti-inflammational treatment options and of preventive interventions.

Are Carbonic Anhydrases Suitable Targets to Fight Protozoan Parasitic Diseases?

2019 ◽  
Vol 25 (39) ◽  
pp. 5266-5278 ◽  
Author(s):  
Katia D'Ambrosio ◽  
Claudiu T. Supuran ◽  
Giuseppina De Simone
Keyword(s):  
Drug Resistance ◽  
Animal Models ◽  
Carbonic Anhydrase ◽  
Drug Target ◽  
Treatment Options ◽  
Parasitic Diseases ◽  
Carbonic Anhydrases ◽  
Extensive Drug Resistance ◽  
Protozoan Infections

Protozoans belonging to Plasmodium, Leishmania and Trypanosoma genera provoke widespread parasitic diseases with few treatment options and many of the clinically used drugs experiencing an extensive drug resistance phenomenon. In the last several years, the metalloenzyme Carbonic Anhydrase (CA, EC 4.2.1.1) was cloned and characterized in the genome of these protozoa, with the aim to search for a new drug target for fighting malaria, leishmaniasis and Chagas disease. P. falciparum encodes for a CA (PfCA) belonging to a novel genetic family, the η-CA class, L. donovani chagasi for a β-CA (LdcCA), whereas T. cruzi genome contains an α-CA (TcCA). These three enzymes were characterized in detail and a number of in vitro potent and selective inhibitors belonging to the sulfonamide, thiol, dithiocarbamate and hydroxamate classes were discovered. Some of these inhibitors were also effective in cell cultures and animal models of protozoan infections, making them of considerable interest for the development of new antiprotozoan drugs with a novel mechanism of action.

scholarly journals Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases

2021 ◽  
Vol 22 (15) ◽  
pp. 8196
Author(s):  
Dorit Trudler ◽  
Swagata Ghatak ◽  
Stuart A. Lipton
Keyword(s):  
Drug Discovery ◽  
Animal Models ◽  
Neurodegenerative Diseases ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Neural Function ◽  
Neural Cells ◽  
Human Samples ◽  
Healthy Donors ◽  
Induced Pluripotent

Neurodegenerative diseases affect millions of people worldwide and are characterized by the chronic and progressive deterioration of neural function. Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), represent a huge social and economic burden due to increasing prevalence in our aging society, severity of symptoms, and lack of effective disease-modifying therapies. This lack of effective treatments is partly due to a lack of reliable models. Modeling neurodegenerative diseases is difficult because of poor access to human samples (restricted in general to postmortem tissue) and limited knowledge of disease mechanisms in a human context. Animal models play an instrumental role in understanding these diseases but fail to comprehensively represent the full extent of disease due to critical differences between humans and other mammals. The advent of human-induced pluripotent stem cell (hiPSC) technology presents an advantageous system that complements animal models of neurodegenerative diseases. Coupled with advances in gene-editing technologies, hiPSC-derived neural cells from patients and healthy donors now allow disease modeling using human samples that can be used for drug discovery.

scholarly journals Challenges in Treating Tardive Dyskinesia: Assessing the Impact of Virtual Medical Education

CNS Spectrums ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 165-165
Author(s):  
Amanda Glazar ◽  
Cecilia Peterson ◽  
Michael Lemon ◽  
Chirag Shah ◽  
Prakash Masand
Keyword(s):  
Medical Education ◽  
Tardive Dyskinesia ◽  
Treatment Options ◽  
Respiratory Muscles ◽  
Educational Activity ◽  
Activity Participation ◽  
Chi Square ◽  
Practice Performance ◽  
New Treatments ◽  
The Impact

AbstractIntroductionTardive Dyskinesia (TD) refers to abnormal, involuntary, choreoathetoid movements of the tongue, lips, face, trunk, and extremities and is associated with long-term exposure to dopamine-blocking agents, such as antipsychotic medications. Once established, these movements usually persist. The movements are disfiguring and can bring unwanted attention to affected individuals. When severe, especially if the respiratory muscles are affected, the movements can be disabling, limit activity, and reduce quality of life. The prevalence is 7.2% in individuals on newer antipsychotics who have never been exposed to older neuroleptics. Until recently, there were no effective treatments for TD. In recent years, many new treatments have been investigated for the treatment of TD, including valbenazine, deutetrabenazine, and branched chain amino acids. Valbenazine first, followed by deutetrabenazine are FDA approved to treat TD. A virtual broadcast was developed to assess the ability of continuing medical education (CME) to improve awareness of the recognition and treatment of TD among psychiatrists.MethodsThe virtual broadcast (May 9, 2020) consisted of a two-hour, live-streamed discussion between two expert faculty. Impact of the educational activity was assessed by comparing psychiatrists’ responses to four identical questions presented before and directly after activity participation. A follow-up survey was sent to all participants six-weeks post-activity to measure performance in practice changes. A chi-square test was used to identify significant differences between pre- and post-assessment responses. Cohen’s d was used to calculate the effect size of the virtual broadcast.ResultsActivity participation resulted in a noticeable educational effect among psychiatrists (n=621; d=6.12, P<.001). The following areas showed significant (P<0.05) pre- vs post-educational improvements: recognition of movements in patients with TD, rate of TD in SGA exposed patients, treatment options for TD (on and off-label), and treatment of TD using VMAT inhibitors. Additionally, 54% of psychiatrists reported a change in practice performance as a result of the education received in the activity, including utilization of a standard scale to evaluate movement disorders and educate patients and family members about potential for TD, how to recognize symptoms, and when to treat.ConclusionsThe results indicated that a CME-certified two-hour virtual broadcast was effective at improving knowledge among psychiatrists for the recognition and treatment of TD. This knowledge also resulted in positive changes in practice performance post-activity. Future education should continue to address best practices in the diagnosis, treatment and management of patients with TD, as there remains an increased need for tailored CME among psychiatrists.FundingNeurocrine Biosciences, Inc.

Review of treatment and therapeutic targets in brain arteriovenous malformation

2021 ◽  
pp. 0271678X2110267
Author(s):  
Peipei Pan ◽  
Shantel Weinsheimer ◽  
Daniel Cooke ◽  
Ethan Winkler ◽  
Adib Abla ◽  
...  
Keyword(s):  
Animal Models ◽  
De Novo ◽  
Mapk Pathway ◽  
Treatment Options ◽  
Therapeutic Targets ◽  
Current Treatment ◽  
Mitogen Activated Protein Kinase ◽  
De Novo Mutations ◽  
Genetic Syndromes ◽  
Mitogen Activated Protein

Brain arteriovenous malformations (bAVM) are an important cause of intracranial hemorrhage (ICH), especially in younger patients. The pathogenesis of bAVM are largely unknown. Current understanding of bAVM etiology is based on studying genetic syndromes, animal models, and surgically resected specimens from patients. The identification of activating somatic mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene and other mitogen-activated protein kinase ( MAPK) pathway genes has opened up new avenues for bAVM study, leading to a paradigm shift to search for somatic, de novo mutations in sporadic bAVMs instead of focusing on inherited genetic mutations. Through the development of new models and understanding of pathways involved in maintaining normal vascular structure and functions, promising therapeutic targets have been identified and safety and efficacy studies are underway in animal models and in patients. The goal of this paper is to provide a thorough review or current diagnostic and treatment tools, known genes and key pathways involved in bAVM pathogenesis to summarize current treatment options and potential therapeutic targets uncovered by recent discoveries.

Treatment Given Near the End of Life in Castration-Resistant Prostate Cancer

2012 ◽  
Vol 29 (7) ◽  
pp. 536-540 ◽  
Author(s):  
Hanna A. Zaghloul ◽  
Jose R. Murillo
Keyword(s):  
Quality Of Life ◽  
Prostate Cancer ◽  
End Of Life ◽  
Treatment Options ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Related Quality ◽  
Impact On Survival ◽  
New Treatments

Chemotherapy treatment options are limited for patients with castration-resistant prostate cancer (CRPC). The purpose of this study is to report treatment use and adverse effects (AEs) within the last three months of life in patients with CRPC. Of the 88 patients identified, 32% received treatment within 3 months of death, and documented AEs occurred in 25% of patients. Of those, neutropenia (18.3%), nausea/vomiting (18.3%), and febrile neutropenia (13.6%) were the most frequent. Results of this study show high treatment utility towards the end-of-life in patients with CRPC, with one fourth of patients experiencing AEs. Attention to health-related quality of life becomes increasingly important as new treatments appear to have small impact on survival, and AEs of those treatments may significantly impact patient quality of life.

New Approaches to Profile the Microbiome for Treatment of Neurodegenerative Disease

2021 ◽  
pp. 1-29
Author(s):  
David R. Elmaleh ◽  
Matthew A. Downey ◽  
Ljiljana Kundakovic ◽  
Jeremy E. Wilkinson ◽  
Ziv Neeman ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Gut Microbiome ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Modern Society ◽  
Aging Brain ◽  
New Approaches ◽  
Microbiome Profile ◽  
Carry Over

Progressive neurodegenerative diseases represent some of the largest growing treatment challenges for public health in modern society. These diseases mainly progress due to aging and are driven by microglial surveillance and activation in response to changes occurring in the aging brain. The lack of efficacious treatment options for Alzheimer’s disease (AD), as the focus of this review, and other neurodegenerative disorders has encouraged new approaches to address neuroinflammation for potential treatments. Here we will focus on the increasing evidence that dysbiosis of the gut microbiome is characterized by inflammation that may carry over to the central nervous system and into the brain. Neuroinflammation is the common thread associated with neurodegenerative diseases, but it is yet unknown at what point and how innate immune function turns pathogenic for an individual. This review will address extensive efforts to identify constituents of the gut microbiome and their neuroactive metabolites as a peripheral path to treatment. This approach is still in its infancy in substantive clinical trials and requires thorough human studies to elucidate the metabolic microbiome profile to design appropriate treatment strategies for early stages of neurodegenerative disease. We view that in order to address neurodegenerative mechanisms of the gut, microbiome and metabolite profiles must be determined to pre-screen AD subjects prior to the design of specific, chronic titrations of gut microbiota with low-dose antibiotics. This represents an exciting treatment strategy designed to balance inflammatory microglial involvement in disease progression with an individual’s manifestation of AD as influenced by a coercive inflammatory gut.

Animal Models of Down Syndrome

2021 ◽  
Author(s):  
Anna J. Moyer ◽  
Roger H. Reeves
Keyword(s):  
Down Syndrome ◽  
Cognitive Impairment ◽  
Intellectual Disability ◽  
Animal Models ◽  
Brain Regions ◽  
Laboratory Mice ◽  
Tremendous Progress ◽  
New Treatments ◽  
And Function ◽  
Early Developmental

Is intellectual disability a treatable feature of persons with Down syndrome? Researchers have made tremendous progress in the last 30 years, from creating the first mouse model of Down syndrome to completing the first major clinical trial for cognitive impairment in people with Down syndrome. Until recently, normalizing brain development and function seemed too lofty a goal, and indeed, even proposing a candidate therapy requires answering a number of difficult questions. How does trisomy 21, a molecular diagnosis, cause the clinical phenotypes of Down syndrome? When, where, and how do trisomic genes act to disrupt normal development and which genes are involved with which outcomes? Which brain regions and behaviors are most impaired? Is there an early developmental window of time during which treatments are most effective? This article discusses how animal models such as laboratory mice can be used to understand intellectual disability and to develop new treatments for cognitive impairment.

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