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Nature Reviews. Neurology Nov 2022The current understanding of neurological diseases is derived mostly from direct analysis of patients and from animal models of disease. However, most patient studies do... (Review)
Review
The current understanding of neurological diseases is derived mostly from direct analysis of patients and from animal models of disease. However, most patient studies do not capture the earliest stages of disease development and offer limited opportunities for experimental intervention, so rarely yield complete mechanistic insights. The use of animal models relies on evolutionary conservation of pathways involved in disease and is limited by an inability to recreate human-specific processes. In vitro models that are derived from human pluripotent stem cells cultured in 3D have emerged as a new model system that could bridge the gap between patient studies and animal models. In this Review, we summarize how such organoid models can complement classical approaches to accelerate neurological research. We describe our current understanding of neurodevelopment and how this process differs between humans and other animals, making human-derived models of disease essential. We discuss different methodologies for producing organoids and how organoids can be and have been used to model neurological disorders, including microcephaly, Zika virus infection, Alzheimer disease and other neurodegenerative disorders, and neurodevelopmental diseases, such as Timothy syndrome, Angelman syndrome and tuberous sclerosis. We also discuss the current limitations of organoid models and outline how organoids can be used to revolutionize research into the human brain and neurological diseases.
Topics: Animals; Humans; Organoids; Brain; Microcephaly; Neurodegenerative Diseases; Zika Virus Infection; Zika Virus; Neurology
PubMed: 36253568
DOI: 10.1038/s41582-022-00723-9 -
JCI Insight Aug 2021Angelman syndrome (AS) is a severe neurodevelopmental disorder for which only symptomatic treatment with limited benefits is available. AS is caused by mutations...
Angelman syndrome (AS) is a severe neurodevelopmental disorder for which only symptomatic treatment with limited benefits is available. AS is caused by mutations affecting the maternally inherited ubiquitin protein ligase E3A (UBE3A) gene. Previous studies showed that the silenced paternal Ube3a gene can be activated by targeting the antisense Ube3a-ATS transcript. We investigated antisense oligonucleotide-induced (ASO-induced) Ube3a-ATS degradation and its ability to induce UBE3A reinstatement and rescue of AS phenotypes in an established Ube3a mouse model. We found that a single intracerebroventricular injection of ASOs at postnatal day 1 (P1) or P21 in AS mice resulted in potent and specific UBE3A reinstatement in the brain, with levels up to 74% of WT levels in the cortex and a full rescue of sensitivity to audiogenic seizures. AS mice treated with ASO at P1 also showed rescue of established AS phenotypes, such as open field and forced swim test behaviors, and significant improvement on the reversed rotarod. Hippocampal plasticity of treated AS mice was comparable to WT but not significantly different from PBS-treated AS mice. No rescue was observed for the marble burying and nest building phenotypes. Our findings highlight the promise of ASO-mediated reactivation of UBE3A as a disease-modifying treatment for AS.
Topics: Angelman Syndrome; Animals; Biological Variation, Population; Disease Models, Animal; Gene Expression Profiling; Gene Silencing; Mice; Oligonucleotides, Antisense; Targeted Gene Repair; Treatment Outcome; Ubiquitin-Protein Ligases
PubMed: 34369389
DOI: 10.1172/jci.insight.145991 -
RNA Biology 2022RNA therapeutics comprise a diverse group of oligonucleotide-based drugs such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and short hairpin...
RNA therapeutics comprise a diverse group of oligonucleotide-based drugs such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs) that can be designed to selectively interact with drug targets currently undruggable with small molecule-based drugs or monoclonal antibodies. Furthermore, RNA-based therapeutics have the potential to modulate entire disease pathways, and thereby represent a new modality with unprecedented potential for generating disease-modifying drugs for a wide variety of human diseases, including central nervous system (CNS) disorders. Here, we describe different strategies for delivering RNA drugs to the CNS and review recent advances in clinical development of ASO drugs and siRNA-based therapeutics for the treatment of neurological diseases and neuromuscular disorders. 2'-MOE: 2'--(2-methoxyethyl); 2'--Me: 2'--methyl; 2'-F: 2'-fluoro; AD: Alzheimer's disease; ALS: Amyotrophic lateral sclerosis; ALSFRS-R: Revised Amyotrophic Lateral Sclerosis Functional Rating Scale; ARC: Antibody siRNA Conjugate; AS: Angelman Syndrome; ASGRP: Asialoglycoprotein receptor; ASO: Antisense oligonucleotide; AxD: Alexander Disease; BBB: Blood brain barrier; Bp: Basepair; CNM: Centronuclear myopathies; CNS: Central Nervous System; CPP: Cell-penetrating Peptide; CSF: Cerebrospinal fluid; DMD: Duchenne muscular dystrophy; DNA: Deoxyribonucleic acid; FAP: Familial amyloid polyneuropathy; FALS: Familial amyotrophic lateral sclerosis; FDA: The United States Food and Drug Administration; GalNAc: N-acetylgalactosamine; GoF: Gain of function; hATTR: Hereditary transthyretin amyloidosis; HD: Huntington's disease; HRQOL: health-related quality of life; ICV: Intracerebroventricular; IT: Intrathecal; LNA: Locked nucleic acid; LoF: Loss of function; mRNA: Messenger RNA; MS: Multiple Sclerosis; MSA: Multiple System Atrophy; NBE: New Biological Entity; NCE: New Chemical Entity; NHP: Nonhuman primate; nt: Nucleotide; PD: Parkinson's disease; PNP: Polyneuropathy; PNS: Peripheral nervous system; PS: Phosphorothioate; RISC: RNA-Induced Silencing Complex; RNA: Ribonucleic acid; RNAi: RNA interference; s.c.: Subcutaneous; siRNA: Small interfering RNA; SMA: Spinal muscular atrophy; SMN: Survival motor neuron; TTR: Transthyretin.
Topics: Animals; Amyloid Neuropathies, Familial; Amyotrophic Lateral Sclerosis; Neuromuscular Diseases; Oligonucleotides, Antisense; Quality of Life; RNA, Messenger; RNA, Small Interfering; United States; Genetic Therapy; Humans; Disease Models, Animal
PubMed: 35482908
DOI: 10.1080/15476286.2022.2066334 -
Neurology Apr 2023The genetic developmental and epileptic encephalopathies (DEEs) comprise a large group of severe epilepsy syndromes, with a wide phenotypic spectrum. Currently, the...
BACKGROUND AND OBJECTIVES
The genetic developmental and epileptic encephalopathies (DEEs) comprise a large group of severe epilepsy syndromes, with a wide phenotypic spectrum. Currently, the rates of convulsive status epilepticus (CSE), nonconvulsive status epilepticus (NCSE), and sudden unexplained death in epilepsy (SUDEP) in these diseases are not well understood. We aimed to describe the proportions of patients with frequently observed genetic DEEs who developed CSE, NCSE, mortality, and SUDEP. Understanding the risks of these serious presentations in each genetic DEE will enable earlier diagnosis and appropriate management.
METHODS
In this retrospective analysis of patients with a genetic DEE, we estimated the proportions with CSE, NCSE, and SUDEP and the overall and SUDEP-specific mortality rates for each genetic diagnosis. We included patients with a pathogenic variant in the genes , , , , , , , , , , and and with Angelman syndrome (AS).
RESULTS
The cohort comprised 510 individuals with a genetic DEE, in whom we observed CSE in 47% and NCSE in 19%. The highest proportion of CSE occurred in patients with -associated DEEs, including 181/203 (89%; 95% CI 84-93) patients with Dravet syndrome and 8/15 (53%; 95% CI 27-79) non-Dravet -DEEs. CSE was also notable in patients with pathogenic variants in (6/10; 60%; 95% CI 26-88) and (8/15; 53%; 95% CI 27-79). NCSE was common in patients with non-Dravet -DEEs (8/15; 53%; 95% CI 27-79) and was notable in patients with -DEEs (6/14; 43%; 95% CI 18-71) and AS (6/19; 32%; 95% CI 13-57). There were 42/510 (8%) deaths among the cohort, producing a mortality rate of 6.1 per 1,000 person-years (95% CI 4.4-8.3). Cases of SUDEP accounted for 19/42 (48%) deaths. Four genes were associated with SUDEP: , , , and The estimated SUDEP rate was 2.8 per 1,000 person-years (95% CI 1.6-4.3).
DISCUSSION
We showed that proportions of patients with CSE, NCSE, and SUDEP differ for commonly encountered genetic DEEs. The estimates for each genetic DEE studied will inform early diagnosis and management of status epilepticus and SUDEP and inform disease-specific counseling for patients and families in this high-risk group of conditions.
Topics: Humans; Retrospective Studies; Sudden Unexpected Death in Epilepsy; Status Epilepticus; Epilepsies, Myoclonic; Epileptic Syndromes; Angelman Syndrome; Death, Sudden; Protocadherins; Potassium Channels, Sodium-Activated; Nerve Tissue Proteins
PubMed: 36750385
DOI: 10.1212/WNL.0000000000207080 -
JAMA Neurology Dec 2022It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes.
IMPORTANCE
It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes.
OBJECTIVE
To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes.
DESIGN, SETTING, AND PARTICIPANTS
This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals.
EXPOSURES
Genetic test results.
MAIN OUTCOMES AND MEASURES
Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms.
RESULTS
Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%).
CONCLUSIONS AND RELEVANCE
Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.
Topics: Humans; Female; Infant, Newborn; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Male; Retrospective Studies; Cross-Sectional Studies; Genetic Testing; Epilepsy; Seizures
PubMed: 36315135
DOI: 10.1001/jamaneurol.2022.3651 -
American Journal on Intellectual and... Jan 2022Angelman Syndrome (AS) is a neurodevelopmental disorder most commonly caused by the impaired expression of the maternal UBE3A gene on chromosome 15. Though anxiety has...
Angelman Syndrome (AS) is a neurodevelopmental disorder most commonly caused by the impaired expression of the maternal UBE3A gene on chromosome 15. Though anxiety has been identified as a frequently present characteristic in AS, there are limited studies examining anxiety in this population. Studies of anxiety in other neurodevelopmental disorders have found disorder specific symptoms of anxiety and age specific displays of anxiety symptoms. However, there is a consistent challenge in identifying anxiety in people with neurodevelopmental disorders given the lack of measurement instruments specifically designed for this population. Given the limited information about AS and anxiety, the aims of the current project were to (a) examine symptoms of anxiety in children with AS and (b) determine the correlates of anxiety in children with AS. Participants included 42 adult caregivers of youth with AS in the AS Natural History study who completed the Developmental Behavior Checklist (DBC). The results found that 26% of the sample demonstrated elevated symptoms of anxiety and established a relationship between elevated anxiety in youth with AS and higher levels of irritability, hyperactivity, self-absorbed behaviors, and disruptive/antisocial behaviors. Findings from this research provide a foundation for tailoring evidence-based assessments and treatments for youth with AS and anxiety.
Topics: Adolescent; Adult; Angelman Syndrome; Anxiety; Caregivers; Checklist; Child; Humans; Neurodevelopmental Disorders
PubMed: 34979033
DOI: 10.1352/1944-7558-127.1.1 -
Journal of Child Neurology May 2023Collectively, neurodevelopmental disorders are highly prevalent, but more than a third of neurodevelopmental disorders have an identifiable genetic etiology, each of... (Review)
Review
Collectively, neurodevelopmental disorders are highly prevalent, but more than a third of neurodevelopmental disorders have an identifiable genetic etiology, each of which is individually rare. The genes associated with neurodevelopmental disorders are often involved in early brain development, neuronal signaling, or synaptic plasticity. Novel treatments for many genetic neurodevelopmental disorders are being developed, but disease-relevant clinical outcome assessments and biomarkers are limited. Electroencephalography (EEG) is a promising noninvasive potential biomarker of brain function. It has been used extensively in epileptic disorders, but its application in neurodevelopmental disorders needs further investigation. In this review, we explore the use of EEG in 3 of the most prevalent genetic neurodevelopmental disorders-Angelman syndrome, Rett syndrome, and fragile X syndrome. Quantitative analyses of EEGs, such as power spectral analysis or measures of connectivity, can quantify EEG signatures seen on qualitative review and potentially correlate with phenotypes. In both Angelman syndrome and Rett syndrome, increased delta power on spectral analysis has correlated with clinical markers of disease severity including developmental disability and seizure burden, whereas spectral power analysis on EEG in fragile X syndrome tends to demonstrate abnormalities in gamma power. Further studies are needed to establish reliable relationships between quantitative EEG biomarkers and clinical phenotypes in rare genetic neurodevelopmental disorders.
Topics: Humans; Rett Syndrome; Angelman Syndrome; Fragile X Syndrome; Electroencephalography; Biomarkers; Neurodevelopmental Disorders
PubMed: 37264615
DOI: 10.1177/08830738231177386 -
Frontiers in Cell and Developmental... 2023Angelman syndrome (AS) is an imprinted neurodevelopmental disorder that lacks a cure, characterized by developmental delay, intellectual impairment, seizures, ataxia,... (Review)
Review
Angelman syndrome (AS) is an imprinted neurodevelopmental disorder that lacks a cure, characterized by developmental delay, intellectual impairment, seizures, ataxia, and paroxysmal laughter. The condition arises due to the loss of the maternally inherited copy of the gene in neurons. The paternally inherited allele is unable to compensate because it is silenced by the expression of an antisense transcript () on the paternal chromosome. , encoding enigmatic E3 ubiquitin ligase variants, regulates target proteins by either modifying their properties/functions or leading them to degradation through the proteasome. Over time, animal models, particularly the Knock-Out (KO) mice, have significantly contributed to our understanding of the molecular mechanisms underlying AS. However, a shift toward human pluripotent stem cell models (PSCs), such as human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), has gained momentum. These stem cell models accurately capture human genetic and cellular characteristics, offering an alternative or a complement to animal experimentation. Human stem cells possess the remarkable ability to recapitulate neurogenesis and generate "brain-in-a-dish" models, making them valuable tools for studying neurodevelopmental disorders like AS. In this review, we provide an overview of the current state-of-the-art human stem cell models of AS and explore their potential to become the preclinical models of choice for drug screening and development, thus propelling AS therapeutic advancements and improving the lives of affected individuals.
PubMed: 37928900
DOI: 10.3389/fcell.2023.1274040