Viral vectors for gene delivery to the central nervous system.

Brain diseases with a known or suspected genetic basis represent an important frontier for advanced therapeutics. The central nervous system (CNS) is an intricate network in which diverse cell types with multiple functions communicate via complex signaling pathways, making therapeutic intervention in brain-related diseases challenging. Nevertheless, as more information on the molecular genetics of brain-related diseases becomes available, genetic intervention using gene therapeutic strategies should become more feasible. There remain, however, several significant hurdles to overcome that relate to (i) the development of appropriate gene vectors and (ii) methods to achieve local or broad vector delivery. Clearly, gene delivery tools must be engineered for distribution to the correct cell type in a specific brain region and to accomplish therapeutic transgene expression at an appropriate level and duration. They also must avoid all toxicity, including the induction of inflammatory responses. Over the last 40 years, various types of viral vectors have been developed as tools to introduce therapeutic genes into the brain, primarily targeting neurons. This review describes the most prominent vector systems currently approaching clinical application for CNS disorders and highlights both remaining challenges as well as improvements in vector designs that achieve greater safety, defined tropism, and therapeutic gene expression.

HLA-transgenic mouse models to study autoimmune central nervous system diseases.

It is known that certain human leukocyte antigen (HLA) genes are associated with autoimmune central nervous system (CNS) diseases, such as multiple sclerosis (MS), but their exact role in disease susceptibility and etiopathogenesis remains unclear. The best studied HLA-associated autoimmune CNS disease is MS, and thus will be the primary focus of this review. Other HLA-associated autoimmune CNS diseases, such as autoimmune encephalitis and neuromyelitis optica will be discussed. The lack of animal models to accurately capture the complex human autoimmune response remains a major challenge. HLA transgenic (tg) mice provide researchers with powerful tools to investigate the underlying mechanisms promoting susceptibility and progression of HLA-associated autoimmune CNS diseases, as well as for elucidating the myelin epitopes potentially targeted by T cells in autoimmune disease patients. We will discuss the potential role(s) of autoimmune disease-associated HLA alleles in autoimmune CNS diseases and highlight information provided by studies using HLA tg mice to investigate the underlying pathological mechanisms and opportunities to use these models for development of novel therapies.

Neurosurgical gene therapy for central nervous system diseases.

Viral vector mediated gene therapies for neurodegenerative and neurodevelopmental conditions that require neurosurgical administration continue to expand. We systematically reviewed the National Institutes of Health (NIH) ClinicalTrials.gov database to identify all clinical trials studying in-vivo viral vector mediated gene therapies targeted to the CNS for neurodegenerative and neurodevelopmental diseases. We isolated studies which delivered therapies using neurosurgical approaches: intracisternal, intraventricular, and/or intraparenchymal. Clinical trials primarily registered in international countries were included if they were referenced by an NIH registered clinical trial. We performed a scoping review to identify the preclinical studies that supported each human clinical trial. Key preclinical and clinical data were aggregated to characterize vector capsid design, delivery methods, gene expression profile, and clinical benefit. A total of 64 clinical trials were identified in active, completed, terminated, and long-term follow-up stages. A range of CNS conditions across pediatric and adult populations are being studied with CNS targeted viral vector gene therapy, including Alzheimer's disease, Parkinson's disease, AADC deficiency, sphingolipidoses, mucopolysaccharidoses, neuronal ceroid lipofuscinoses, spinal muscular atrophy, adrenoleukodystrophy, Canavan disease, frontotemporal dementia, Huntington's disease, Rett syndrome, Dravet syndrome, mesial temporal lobe epilepsy, and glutaric acidemia. Adeno-associated viral vectors (AAVs) were utilized by the majority of tested therapies, with vector serotypes, regulatory elements, delivery methods, and vector monitoring varying based on the disease being studied. Intraparenchymal delivery has evolved significantly, with MRI-guided convection-enhanced delivery established as a gold standard method for pioneering novel gene targets.

The Role of RNA m5C Modification in Central Nervous System Diseases.

As advances in RNA modification research progress, the significance of 5-methylcytosine (m5C) modification is being increasingly acknowledged. m5C undergoes modification by the methyltransferase NOP2/Sun domain (NSUN) family/DNA methyltransferase (DNMT) family (writer) and is removed by demethylases (eraser), including the ten-eleven translocation (TET) family and Alkb homolog 1 (ALKBH1). Moreover, m5C interacts with RNA-binding proteins (reader), such as Y-box-binding protein 1 (YBX1) and Aly/REF export factor (ALYREF). Expanding on this structural framework, m5C modification possesses the capacity to regulate various physiological and pathological processes. Recent studies indicate that m5C plays a pivotal regulatory role in the central nervous system, and its dysregulation may correlate with the onset and progression of various central nervous system diseases. In this review, we summarize recent research on m5C components and delve into the potential mechanisms of m5C involvement in central nervous system disorders, such as Alzheimer's disease, brain tumors, epilepsy, and stroke.

MicroRNA-based interventions in aberrant cell cycle diseases: Therapeutic strategies for cancers, central nervous system disorders and comorbidities.

Malignant tumors and central nervous system (CNS) disorders are intricately linked to a process known as "aberrant cell cycle re-entry," which plays a critical role in the progression of these diseases. Addressing the dysregulation in cell cycles offers a promising therapeutic approach for cancers and CNS disorders. MicroRNAs (miRNAs) play a crucial role as regulators of gene expression in cell cycle transitions, presenting a promising therapeutic avenue for treating these disorders and their comorbidities. This review consolidates the progress made in the last three years regarding miRNA-based treatments for diseases associated with aberrant cell cycle re-entry. It encompasses exploring fundamental mechanisms and signaling pathways influenced by miRNAs in cancers and CNS disorders, particularly focusing on the therapeutic effects of exosome-derived miRNAs. The review also identifies specific miRNAs implicated in comorbidity of cancers and CNS disorders, discusses the future potential of miRNA reagents in managing cell cycle-related diseases.

Perspective and Therapeutic Potential of the Noncoding RNA-Connexin Axis.

Noncoding RNAs (ncRNAs) are a class of nucleotide sequences that cannot be translated into peptides. ncRNAs can function post-transcriptionally by splicing complementary sequences of mRNAs or other ncRNAs or by directly engaging in protein interactions. Over the past few decades, the pervasiveness of ncRNAs in cell physiology and their pivotal roles in various diseases have been identified. One target regulated by ncRNAs is connexin (Cx), a protein that forms gap junctions and hemichannels and facilitates intercellular molecule exchange. The aberrant expression and misdistribution of connexins have been implicated in central nervous system diseases, cardiovascular diseases, bone diseases, and cancer. Current databases and technologies have enabled researchers to identify the direct or indirect relationships between ncRNAs and connexins, thereby elucidating their correlation with diseases. In this review, we selected the literature published in the past five years concerning disorders regulated by ncRNAs via corresponding connexins. Among it, microRNAs that regulate the expression of Cx43 play a crucial role in disease development and are predominantly reviewed. The distinctive perspective of the ncRNA-Cx axis interprets pathology in an epigenetic manner and is expected to motivate research for the development of biomarkers and therapeutics.

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To date, approximately 500 monogenic inherited kidney diseases have been reported, with more than 50 genes associated with the pathogenesis of monogenic isolated or syndromic nephrotic syndrome. Most of these genes are expressed in podocytes of the glomerulus. Neurological symptoms are common extrarenal manifestations of syndromic nephrotic syndrome, and various studies have found connections between podocytes and neurons in terms of morphology and function. This review summarizes the genetic and clinical characteristics of monogenic inherited diseases with concomitant glomerular and central nervous system lesions, aiming to enhance clinicians' understanding of such diseases, recognize the importance of genetic diagnostic techniques for comorbidity screening, and reduce the rates of missed diagnosis and misdiagnosis.

Gene therapy for CNS disorders: modalities, delivery and translational challenges.

Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.

Central nervous system anomalies in 41 Chinese children incontinentia pigmenti.

INTRODUCTION: Incontinentia pigmenti (IP) is a rare neuroectodermal dysplasia caused by a defect in the IKBKG gene. The pathogenesis of central nervous system injury is believed to be related to microvascular ischemia. Currently, few treatment strategies are available for the inflammatory phase. MATERIALS AND METHODS: This retrospective descriptive analysis included the clinical data of 41 children with IP collected from 2007 to 2021 in Xi'an, China, comprising clinical characteristics, imaging findings, blood cell analysis, skin histopathology, and genetic data. RESULTS: Fourteen children (34%) aged 4 days to 5 months exhibited clinical signs and symptoms, including convulsions, delayed psychomotor development following neurological damage, and revealed significant MRI abnormalities, including ischemia, hypoxia, cerebral hypoperfusion, hemorrhage, encephalomalacia, and cerebral atrophy. Eight of the 24 patients (33%) presented with retinal vascular tortuosity and telangiectasis, accompanied by neovascularization and hemorrhage. Thirty-eight children (93%) had elevated eosinophils (mean: 3.63 ± 4.46 × 109), and 28 children (68%) had significantly elevated platelets (mean: 420.16 ± 179.43 × 109). Histopathology of skin revealed microvascular extravasation and vasodilation with perivascular and intravascular eosinophilic infiltration. CONCLUSION: Brain injury in IP occurs during infancy until 5 months of age, which is also the acute dermatitis phase accompanied by eosinophilia and an increased platelet count. This study provides evidence of microvascular damage to the skin and fundus during the inflammatory phase. The mechanism of microvascular damage may be similar to that in the brain.

In Vivo Reprogramming Using Yamanaka Factors in the CNS: A Scoping Review.

Central nervous system diseases, particularly neurodegenerative disorders, pose significant challenges in medicine. These conditions, characterized by progressive neuronal loss, have remained largely incurable, exacting a heavy toll on individuals and society. In recent years, in vivo reprogramming using Yamanaka factors has emerged as a promising approach for central nervous system regeneration. This technique involves introducing transcription factors, such as Oct4, Sox2, Klf4, and c-Myc, into adult cells to induce their conversion into neurons. This review summarizes the current state of in vivo reprogramming research in the central nervous system, focusing on the use of Yamanaka factors. In vivo reprogramming using Yamanaka factors has shown promising results in several animal models of central nervous system diseases. Studies have demonstrated that this approach can promote the generation of new neurons, improve functional outcomes, and reduce scar formation. However, there are still several challenges that need to be addressed before this approach can be translated into clinical practice. These challenges include optimizing the efficiency of reprogramming, understanding the cell of origin for each transcription factor, and developing methods for reprogramming in non-subventricular zone areas. Further research is needed to overcome the remaining challenges, but this approach has the potential to revolutionize the way we treat central nervous system disorders.

Roles of HOTAIR Long Non-coding RNA in Gliomas and Other CNS Disorders.

HOX transcript antisense intergenic RNA (HOTAIR) is a long non-coding RNA (lncRNA) which is increasingly being perceived as a tremendous molecular mediator of brain pathophysiology at multiple levels. Epigenetic regulation of target gene expression carried out by HOTAIR is thorough modulation of chromatin modifiers; histone methyltransferase polycomb repressive complex 2 (PRC2) and histone demethylase lysine-specific demethylase 1 (LSD1). Incidentally, HOTAIR was the first lncRNA shown to elicit sponging of specific microRNA (miRNA or miR) species in a trans-acting manner. It has been extensively studied in various cancers, including gliomas and is regarded as a prominent pro-tumorigenic and pro-oncogenic lncRNA. Indeed, the expression of HOTAIR may serve as glioma grade predictor and prognostic biomarker. The objective of this timely review is not only to outline the multifaceted pathogenic roles of HOTAIR in the development and pathophysiology of gliomas and brain cancers, but also to delineate the research findings implicating it as a critical regulator of overall brain pathophysiology. While the major focus is on neuro-oncology, wherein HOTAIR represents a particularly potent underlying pathogenic player and a suitable therapeutic target, mechanisms underlying the regulatory actions of HOTAIR in neurodegeneration, traumatic, hypoxic and ischemic brain injuries, and neuropsychiatric disorders are also presented.

Single-Cell Sequencing Technology and Its Application in the Study of Central Nervous System Diseases.

The mammalian central nervous system consists of a large number of cells, which contain not only different types of neurons, but also a large number of glial cells, such as astrocytes, oligodendrocytes, and microglia. These cells are capable of performing highly refined electrophysiological activities and providing the brain with functions such as nutritional support, information transmission and pathogen defense. The diversity of cell types and individual differences between cells have brought inspiration to the study of the mechanism of central nervous system diseases. In order to explore the role of different cells, a new technology, single-cell sequencing technology has emerged to perform specific analysis of high-throughput cell populations, and has been continuously developed. Single-cell sequencing technology can accurately analyze single-cell expression in mixed-cell populations and collect cells from different spatial locations, time stages and types. By using single-cell sequencing technology to compare gene expression profiles of normal and diseased cells, it is possible to discover cell subsets associated with specific diseases and their associated genes. Therefore, scientists can understand the development process, related functions and disease state of the nervous system from an unprecedented depth. In conclusion, single-cell sequencing technology provides a powerful technology for the discovery of novel therapeutic targets for central nervous system diseases.

Astrocytes in human central nervous system diseases: a frontier for new therapies.

Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence of the central nervous system (CNS). Astroglia contribute to the pathophysiology of all neurological and neuropsychiatric disorders in ways that can be either beneficial or detrimental to disorder outcome. Pathophysiological changes in astroglia can be primary or secondary and can result in gain or loss of functions. Astroglia respond to external, non-cell autonomous signals associated with any form of CNS pathology by undergoing complex and variable changes in their structure, molecular expression, and function. In addition, internally driven, cell autonomous changes of astroglial innate properties can lead to CNS pathologies. Astroglial pathophysiology is complex, with different pathophysiological cell states and cell phenotypes that are context-specific and vary with disorder, disorder-stage, comorbidities, age, and sex. Here, we classify astroglial pathophysiology into (i) reactive astrogliosis, (ii) astroglial atrophy with loss of function, (iii) astroglial degeneration and death, and (iv) astrocytopathies characterised by aberrant forms that drive disease. We review astroglial pathophysiology across the spectrum of human CNS diseases and disorders, including neurotrauma, stroke, neuroinfection, autoimmune attack and epilepsy, as well as neurodevelopmental, neurodegenerative, metabolic and neuropsychiatric disorders. Characterising cellular and molecular mechanisms of astroglial pathophysiology represents a new frontier to identify novel therapeutic strategies.

Circular RNAs: Diagnostic and Therapeutic Perspectives in CNS Diseases.

Circular RNAs (circRNAs) are a class of regulatory non-coding RNAs characterized by the presence of covalently closed ends. A growing body of evidence suggests that circRNAs play important roles in physiology and pathology. In particular, accumulating data on circRNA functions in various central nervous system (CNS) diseases and their correlations indicate that circRNAs are critical contributors to the onset and development of brain disorders. In this review, we focus on the regulatory and functional roles of circRNAs in CNS diseases, highlighting their diagnostic and therapeutic potential, with the aim of providing new insights into CNS diseases.

Comparative neurogenetics of dog behavior complements efforts towards human neuropsychiatric genetics.

Domestic dogs display a wide array of heritable behaviors that have intermediate genetic complexity thanks to a long history of human-influenced selection. Comparative genetics in dogs could address the scarcity of non-human neurogenetic systems relevant to human neuropsychiatric disorders, which are characterized by mental, emotional, and behavioral symptoms and involve vastly complex genetic and non-genetic risk factors. Our review describes the diverse behavioral "phenome" of domestic dogs, past and ongoing sources of behavioral selection, and the state of canine behavioral genetics. We highlight two naturally disordered behavioral domains that illustrate how dogs may prove useful as a comparative, forward neurogenetic system: canine age-related cognitive dysfunction, which can be examined more rapidly given the attenuated lifespan of dogs, and compulsive disorders, which may have genetic roots in purpose-bred behaviors. Growing community science initiatives aimed at the companion dog population will be well suited to investigating such complex behavioral phenotypes and offer a comparative resource that parallels human genomic initiatives in scale and dimensionality.

Gut microbes influence the development of central nervous system disorders through epigenetic inheritance.

Central nervous system (CNS) disorders, such as depression, anxiety, and Alzheimer's disease (AD), affect quality of life of patients and pose significant economic and social burdens worldwide. Due to their obscure and complex pathogeneses, current therapies for these diseases have limited efficacy. Over the past decade, the gut microbiome has been shown to exhibit direct and indirect influences on the structure and function of the CNS, affecting multiple pathological pathways. In addition to the direct interactions between the gut microbiota and CNS, the gut microbiota and their metabolites can regulate epigenetic processes, including DNA methylation, histone modification, and regulation of non-coding RNAs. In this review, we discuss the tripartite relationship among gut microbiota, epigenetic inheritance, and CNS disorders. We suggest that gut microbes and their metabolites influence the pathogenesis of CNS disorders at the epigenetic level, which may inform the development of effective therapeutic strategies for CNS disorders.

New Insights into the Roles of p53 in Central Nervous System Diseases.

The transcription factor p53, a widely accepted tumor suppressor, regulates the expression of many oncogenes and their downstream signaling pathways, resulting in a series of biological outcomes. Mutations and deletions of the p53 gene often occur in tumor tissues and are involved in their development. In addition to its role in tumors, p53 has a widespread expression in the brain and participates in most cell processes, such as dendrite formation, oxidative stress, apoptosis, autophagy, DNA repair, and cell cycle arrest. Therefore, abnormalities in p53 and its related signaling pathways play an important role in the diagnosis and treatment of central nervous system diseases. This review mainly discusses the latest findings regarding the role of p53 in some central nervous system diseases, such as brain tumors, Alzheimer disease, Parkinson disease, autism, epilepsy, spinocerebellar ataxia, and so on, to provide a comprehensive interpretation of the treatment of neurological diseases from a new perspective.

Large-Scale Integration of Single-Cell RNA-Seq Data Reveals Astrocyte Diversity and Transcriptomic Modules across Six Central Nervous System Disorders.

The dysfunction of astrocytes in response to environmental factors contributes to many neurological diseases by impacting neuroinflammation responses, glutamate and ion homeostasis, and cholesterol and sphingolipid metabolism, which calls for comprehensive and high-resolution analysis. However, single-cell transcriptome analyses of astrocytes have been hampered by the sparseness of human brain specimens. Here, we demonstrate how large-scale integration of multi-omics data, including single-cell and spatial transcriptomic and proteomic data, overcomes these limitations. We created a single-cell transcriptomic dataset of human brains by integration, consensus annotation, and analyzing 302 publicly available single-cell RNA-sequencing (scRNA-seq) datasets, highlighting the power to resolve previously unidentifiable astrocyte subpopulations. The resulting dataset includes nearly one million cells that span a wide variety of diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), epilepsy (Epi), and chronic traumatic encephalopathy (CTE). We profiled the astrocytes at three levels, subtype compositions, regulatory modules, and cell-cell communications, and comprehensively depicted the heterogeneity of pathological astrocytes. We constructed seven transcriptomic modules that are involved in the onset and progress of disease development, such as the M2 ECM and M4 stress modules. We validated that the M2 ECM module could furnish potential markers for AD early diagnosis at both the transcriptome and protein levels. In order to accomplish a high-resolution, local identification of astrocyte subtypes, we also carried out a spatial transcriptome analysis of mouse brains using the integrated dataset as a reference. We found that astrocyte subtypes are regionally heterogeneous. We identified dynamic cell-cell interactions in different disorders and found that astrocytes participate in key signaling pathways, such as NRG3-ERBB4, in epilepsy. Our work supports the utility of large-scale integration of single-cell transcriptomic data, which offers new insights into underlying multiple CNS disease mechanisms where astrocytes are involved.

Clinical gene therapy development for the central nervous system: Candidates and challenges for AAVs.

Many diseases affecting the central nervous system (CNS) are deadly but less understood, leading to impaired mental and motor capabilities and poor patient prospects. Gene therapy is a promising therapeutic modality for correcting many genetic disorders, expanding in breadth and scope with further advances. This review summarizes the candidate CNS disorders for gene therapy, mechanisms of gene therapy, and recent clinical advances and limitations of gene therapy in CNS disorders. We highlight that improving delivery across CNS barriers, safety, monitoring techniques, and multiplexing therapies are predominant factors in advancing long-term outcomes from gene therapy.

RNA regulation of inflammatory responses in glia and its potential as a therapeutic target in central nervous system disorders.

A major hallmark of neuroinflammation is the activation of microglia and astrocytes with the induction of inflammatory mediators such as IL-1ß, TNF-α, iNOS, and IL-6. Neuroinflammation contributes to disease progression in a plethora of neurological disorders ranging from acute CNS trauma to chronic neurodegenerative disease. Posttranscriptional pathways of mRNA stability and translational efficiency are major drivers for the expression of these inflammatory mediators. A common element in this level of regulation centers around the adenine- and uridine-rich element (ARE) which is present in the 3' untranslated region (UTR) of the mRNAs encoding these inflammatory mediators. (ARE)-binding proteins (AUBPs) such as Human antigen R (HuR), Tristetraprolin (TTP) and KH- type splicing regulatory protein (KSRP) are key nodes for directing these posttranscriptional pathways and either promote (HuR) or suppress (TTP and KSRP) glial production of inflammatory mediators. This review will discuss basic concepts of ARE-mediated RNA regulation and its impact on glial-driven neuroinflammatory diseases. We will discuss strategies to target this novel level of gene regulation for therapeutic effect and review exciting preliminary studies that underscore its potential for treating neurological disorders.