4.7 Review

Gene-based therapeutics for rare genetic neurodevelopmental psychiatric disorders

Related references

Note: Only part of the references are listed.
Article Neurosciences

AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset

David Goertsen et al.

Summary: The study developed AAV capsids that achieved robust transgene expression in the brain with decreased liver targeting after non-invasive administration, enabling more targeted systemic gene delivery. This organ-specific targeting extends to marmosets, allowing for non-invasive gene delivery with distinct transgene expression patterns. The ability to cross the blood-brain barrier with neuronal specificity in rodents and non-human primates opens up new avenues for basic research and therapeutic possibilities beyond naturally occurring serotypes.

NATURE NEUROSCIENCE (2022)

Article Multidisciplinary Sciences

Rare coding variants in ten genes confer substantial risk for schizophrenia

Tarjinder Singh et al.

Summary: Rare coding variants in certain genes, particularly those related to the function of the nervous system, are found to be significantly associated with schizophrenia. The involvement of specific receptor subunits in the glutamatergic system supports the hypothesis of dysfunction in this system as a mechanism in the development of schizophrenia. The findings suggest that both common and rare genetic risk factors are involved in the pathogenesis of schizophrenia, and more risk genes are yet to be discovered using this approach.

NATURE (2022)

Review Medicine, Research & Experimental

Overcoming innate immune barriers that impede AAV gene therapy vectors

Manish Muhuri et al.

Summary: Research has shown that host immune responses against rAAVs have hindered the progress of gene therapy. Both the innate and adaptive arms of the immune system play a role in this response.

JOURNAL OF CLINICAL INVESTIGATION (2021)

Review Endocrinology & Metabolism

Crossing the blood-brain barrier with AAV vectors

Dan Liu et al.

Summary: This article discusses the challenges in treating CNS diseases due to the limitations imposed by the blood-brain barrier (BBB) and explores how adeno-associated virus (AAV) vectors can potentially overcome this barrier. It highlights the advancements in AAV9 directed evolution and the development of variants with higher crossing efficiency, as well as the ongoing research on AAV crossing the BBB and transduction mechanisms. Additionally, methods to enhance AAV transduction efficiency are also addressed.

METABOLIC BRAIN DISEASE (2021)

Article Biotechnology & Applied Microbiology

Capsid-Engineering for Central Nervous System-Directed Gene Therapy with Adeno-Associated Virus Vectors

Josephine Macdonald et al.

Summary: Advancements in understanding the causes of neurodegenerative disorders are driving innovative treatment strategies, with gene therapy emerging as a top candidate. Efforts are focused on improving gene therapy delivery tools, particularly recombinant adenoassociated virus (AAV) vectors.

HUMAN GENE THERAPY (2021)

Article Biochemistry & Molecular Biology

Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue

Gretchen Thomsen et al.

Summary: Biodistribution analysis of two patients with spinal muscular atrophy shows widespread onasemnogene abeparvovec DNA, mRNA and SMN protein throughout the central nervous system and peripheral organs following intravenous gene therapy administration. Both patients experienced varying outcomes after receiving the treatment, including improved motor function in one patient and death in the other shortly after administration. The study demonstrates effective distribution, transduction, and expression of onasemnogene abeparvovec throughout the CNS, supporting its potential for restoring SMN expression in individuals with SMA1.

NATURE MEDICINE (2021)

Article Biotechnology & Applied Microbiology

Deep diversification of an AAV capsid protein by machine learning

Drew H. Bryant et al.

Summary: The study uses deep learning to design highly diverse AAV2 capsid protein variants viable for packaging DNA payload, surpassing the average diversity of natural AAV serotype sequences. Deep neural network models accurately predict capsid viability across diverse variants even when trained on limited data, unlocking previously unreachable sequence space with many potential applications.

NATURE BIOTECHNOLOGY (2021)

Article Medicine, General & Internal

Risdiplam in Type 1 Spinal Muscular Atrophy

Giovanni Baranello et al.

Summary: In a study involving 21 infants with type 1 spinal muscular atrophy, treatment with oral risdiplam resulted in increased levels of functional SMN protein in the blood. Infants in the high-dose group were more likely to sit without support for at least 5 seconds, and the higher dose of risdiplam was selected for the second part of the study.

NEW ENGLAND JOURNAL OF MEDICINE (2021)

Article Medicine, Research & Experimental

Rapid evolution of blood-brain-barrier-penetrating AAV capsids by RNA-driven biopanning

Mathieu Nonnenmacher et al.

Summary: A new RNA-driven screening platform called TRACER has been developed to rapidly select AAV capsids with robust BBB penetration and CNS tropism in nontransgenic animals. This method effectively addresses the challenge of therapeutic payload delivery to the central nervous system.

MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT (2021)

Article Clinical Neurology

Engineered microRNA-based regulatory element permits safe high-dose miniMECP2 gene therapy in Rett mice

Sarah E. Sinnett et al.

Summary: The study shows that controlling the overexpression of MECP2 remains a critical obstacle in gene therapy for Rett syndrome. By developing a risk-driven viral genome design strategy and inserting miRARE into the miniMECP2 gene expression cassette, the safety of gene transfer was greatly improved without compromising efficacy, suggesting a potential use in gene therapy for other dose-sensitive genes.

BRAIN (2021)

Review Biochemistry & Molecular Biology

Nonsense suppression therapies in human genetic diseases

Patricia Martins-Dias et al.

Summary: Nonsense mutations can lead to dysfunctional proteins, but nonsense suppression therapy has the potential to restore protein function and treat a variety of genetic disorders. However, the efficiency of suppression may be influenced by nonsense-mediated decay, highlighting the importance of using NMD inhibitors or readthrough-compound potentiators to enhance therapeutic effects.

CELLULAR AND MOLECULAR LIFE SCIENCES (2021)

Article Genetics & Heredity

Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder

Behrang Mahjani et al.

Summary: In this study, rare potentially damaging single nucleotide variations (pdSNV) were found to be more common than potentially damaging copy number variations (pdCNV) in ASD patients. The combined yield of potentially damaging variations was substantial at 27%, indicating the importance of high-throughput sequencing in routine clinical workup for ASD.

MOLECULAR AUTISM (2021)

Article Clinical Neurology

Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial

John W. Day et al.

Summary: The study evaluated the safety and efficacy of onasemnogene abeparvovec gene therapy in symptomatic patients with infantile-onset spinal muscular atrophy. Results showed that patients achieved independent sitting and survival rates without permanent ventilation at certain time points, with a favorable benefit-risk profile supporting the use of onasemnogene abeparvovec for treatment of this condition.

LANCET NEUROLOGY (2021)

Article Multidisciplinary Sciences

Presymptomatic training mitigates functional deficits in a mouse model of Rett syndrome

Nathan P. Achilly et al.

Summary: Research using a mouse model of Rett syndrome shows that intensive training before symptom onset can significantly improve specific motor and memory tasks, delaying the onset of symptoms. The study indicates that task-specific neurons activated during training develop more dendritic arbors and have better neurophysiological responses, enhancing their functionality and delaying symptom onset.

NATURE (2021)

Article Immunology

Novel Combinatorial MicroRNA-Binding Sites in AAV Vectors Synergistically Diminish Antigen Presentation and Transgene Immunity for Efficient and Stable Transduction

Manish Muhuri et al.

Summary: The use of miRNA binding sites in rAAV vectors has shown promise in reducing transgene immunity and achieving sustained transgene expression in muscle cells. Combinatorial miR-142BS and miR-652-5pBS have been effective in inhibiting transgene expression in APCs, while maintaining high expression in muscle cells.

FRONTIERS IN IMMUNOLOGY (2021)

Article Biochemistry & Molecular Biology

Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species

Mohammadsharif Tabebordbar et al.

Summary: Evolved capsid variants of AAVs show enhanced potency and therapeutic efficacy for delivering genetic modifiers to muscle tissues, surpassing naturally occurring AAV capsids in mouse models of genetic muscle disease. These engineered vectors demonstrate conserved efficacy across different mouse strains, cynomolgus macaques, and human primary myotubes, indicating a promising approach for gene therapy.
Article Genetics & Heredity

Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG)

Kandamurugu Manickam et al.

Summary: The research supports the positive effects of ES/GS on clinical management of patients with CA/DD/ID and on family and reproductive outcomes; compared with standard genetic testing, ES/GS has a higher diagnostic yield and may be more cost-effective.

GENETICS IN MEDICINE (2021)

Article Biotechnology & Applied Microbiology

A comprehensive study of a 29-capsid AAV library in a non-human primate central nervous system

Oleksandr Kondratov et al.

Summary: The study utilized a multiplex barcode recombinant AAV vector-tracing strategy to analyze 29 distinct AAV natural isolates and engineered capsids in the central nervous system of eight macaques, identifying the most efficient AAV capsid variants targeting specific CNS areas under different delivery routes. Newly developed bioinformatics and visualization algorithms for comparative analysis of mammalian brain models have been made publicly available.

MOLECULAR THERAPY (2021)

Review Biotechnology & Applied Microbiology

Next-generation strategies for gene-targeted therapies of central nervous system disorders: A workshop summary

Jill A. Morris et al.

Summary: NINDS organized a workshop on gene-targeted therapies for CNS disorders, bringing together experts from various fields to identify challenges and propose solutions. Prior to the workshop, key obstacles and research gaps were identified through pre-meeting teleconferences, allowing for problem-solving discussions and strategy development at the workshop.

MOLECULAR THERAPY (2021)

Article Neurosciences

Exome sequencing in obsessive-compulsive disorder reveals a burden of rare damaging coding variants

Mathew Halvorsen et al.

Summary: An analysis of the largest exome sequencing dataset of individuals with obsessive-compulsive disorder reveals that rare damaging coding variants play a role in disease risk, as supported by both case-control and de novo variant studies. This study provides insights into the genetic factors contributing to OCD and highlights the significance of rare coding variants in its development.

NATURE NEUROSCIENCE (2021)

Review Multidisciplinary Sciences

Discovery and implications of polygenicity of common diseases

Peter M. Visscher et al.

Summary: The sequencing of the human genome has allowed the study of the genetic architecture of common diseases, revealing that common diseases are polygenic and the cumulative effects of risk alleles determine individual risk. By quantifying these effects as a polygenic score, individuals at increased risk of disease can be identified for prevention or early intervention.

SCIENCE (2021)

Article Biology

AAV ablates neurogenesis in the adult murine hippocampus

Stephen Johnston et al.

Summary: The study demonstrated that neural progenitor cells and immature dentate granule cells in the adult murine hippocampus are highly sensitive to rAAV-induced cell death, which is dose-dependent and nearly complete at experimentally relevant viral titers. rAAV-induced cell death is rapid and persistent, with no evidence of recovery of adult neurogenesis at 3 months post-injection.

ELIFE (2021)

Review Medicine, General & Internal

Emerging Immunogenicity and Genotoxicity Considerations of Adeno-Associated Virus Vector Gene Therapy for Hemophilia

Paul E. Monahan et al.

Summary: Gene therapy using AAV vectors has shown promise as a potential cure for hemophilia, but immune responses remain a challenge. Various strategies have been explored to overcome immunogenicity and immune response issues, but more efficient methods are needed to deliver lasting, predictable outcomes.

JOURNAL OF CLINICAL MEDICINE (2021)

Article Multidisciplinary Sciences

Regulated control of gene therapies by drug-induced splicing

Alex Mas Monteys et al.

Summary: A universal switch element has been developed for precise control of gene replacement or editing machinery after exposure to small molecules. This switch system, called X-on, allows controlled protein expression by adjusting drug dose, protein stability, and redosing. It offers an opportunity to refine and tailor gene therapies in humans due to its oral bioavailability and safety of the drugs used.

NATURE (2021)

Review Biochemistry & Molecular Biology

Viral vector platforms within the gene therapy landscape

Jote T. Bulcha et al.

Summary: The field of gene therapy has made significant progress in combating human diseases and providing hope to patients and families with limited treatment options, but it has also faced setbacks. Viral-based vectors have played a crucial role in developing powerful drug platforms, but challenges still limit their full potential.

SIGNAL TRANSDUCTION AND TARGETED THERAPY (2021)

Article Psychology, Developmental

Measuring What Matters to Individuals with Angelman Syndrome and Their Families: Development of a Patient-Centered Disease Concept Model

Tom Willgoss et al.

Summary: A comprehensive study on Angelman syndrome (AS) was conducted to identify the impact of symptoms on individuals and their unmet need. Key AS concepts relevant for treatment include impaired communication, seizures, maladaptive behavior, cognitive impairment, motor difficulties, sleep disturbance, and limited self-care abilities. The study found differences in perceptions between clinicians and caregivers towards the syndrome.

CHILD PSYCHIATRY & HUMAN DEVELOPMENT (2021)

Article Biotechnology & Applied Microbiology

A Safe and Reliable Technique for CNS Delivery of AAV Vectors in the Cisterna Magna

Toloo Taghian et al.

MOLECULAR THERAPY (2020)

Editorial Material Biotechnology & Applied Microbiology

Codon Modification and PAMPs in Clinical AAV Vectors: The Tortoise or the Hare?

J. Fraser Wright

MOLECULAR THERAPY (2020)

Review Genetics & Heredity

Engineering adeno-associated virus vectors for gene therapy

Chengwen Li et al.

NATURE REVIEWS GENETICS (2020)

Review Neurosciences

Angelman Syndrome: From Mouse Models to Therapy

Diana C. Rotaru et al.

NEUROSCIENCE (2020)

Letter Biotechnology & Applied Microbiology

Re: Moving Forward After Two Deaths in a Gene Therapy Trial of Myotubular Myopathy by Wilson and Flotte

Perry B. Shieh et al.

HUMAN GENE THERAPY (2020)

Editorial Material Biotechnology & Applied Microbiology

Moving Forward After Two Deaths in a Gene Therapy Trial of Myotubular Myopathy

James M. Wilson et al.

HUMAN GENE THERAPY (2020)

Article Medicine, General & Internal

SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS

Christian Mueller et al.

NEW ENGLAND JOURNAL OF MEDICINE (2020)

Review Neurosciences

Neurodevelopmental Disorders: From Genetics to Functional Pathways

Ilaria Parenti et al.

TRENDS IN NEUROSCIENCES (2020)

Article Multidisciplinary Sciences

Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression

Kian Huat Lim et al.

NATURE COMMUNICATIONS (2020)

Article Biotechnology & Applied Microbiology

Quantitative Whole-Body Imaging of I-124-Labeled Adeno-Associated Viral Vector Biodistribution in Nonhuman Primates

Douglas J. Ballon et al.

HUMAN GENE THERAPY (2020)

Article Genetics & Heredity

Identification of common genetic risk variants for autism spectrum disorder

Jakob Grove et al.

NATURE GENETICS (2019)

Review Biotechnology & Applied Microbiology

Adeno-associated virus vector as a platform for gene therapy delivery

Dan Wang et al.

NATURE REVIEWS DRUG DISCOVERY (2019)

Editorial Material Medicine, Research & Experimental

Rational Design of Gene Therapy Vectors

Dao Pan et al.

MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT (2019)

Article Genetics & Heredity

Recessive gene disruptions in autism spectrum disorder

Ryan N. Doan et al.

NATURE GENETICS (2019)

Article Multidisciplinary Sciences

A systematic capsid evolution approach performed in vivo for the design of AAV vectors with tailored properties and tropism

Marcus Davidsson et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2019)

Article Genetics & Heredity

Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum

Andrea Ganna et al.

AMERICAN JOURNAL OF HUMAN GENETICS (2018)

Article Genetics & Heredity

X-linked intellectual disability update 2017

Giovanni Neri et al.

AMERICAN JOURNAL OF MEDICAL GENETICS PART A (2018)

Article Biotechnology & Applied Microbiology

Overcoming Limitations Inherent in Sulfamidase to Improve Mucopolysaccharidosis IIIA Gene Therapy

Yonghong Chen et al.

MOLECULAR THERAPY (2018)

Article Biotechnology & Applied Microbiology

Bioengineered AAV Capsids with Combined High Human Liver Transduction In Vivo and Unique Humoral Seroreactivity

Nicole K. Paulk et al.

MOLECULAR THERAPY (2018)

Article Biotechnology & Applied Microbiology

Standardized Method for Intra-Cisterna Magna Delivery Under Fluoroscopic Guidance in Nonhuman Primates

Nathan Katz et al.

HUMAN GENE THERAPY METHODS (2018)

Article Medicine, Research & Experimental

A Rationally Engineered Capsid Variant of AAV9 for Systemic CNS-Directed and Peripheral Tissue-Detargeted Gene Delivery in Neonates

Dan Wang et al.

MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT (2018)

Article Medicine, Research & Experimental

Toxicology Study of Intra-Cisterna Magna Adeno-Associated Virus 9 Expressing Human Alpha-L-Iduronidase in Rhesus Macaques

Juliette Hordeaux et al.

MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT (2018)

Review Biotechnology & Applied Microbiology

Gene therapy for neurological disorders: progress and prospects

Benjamin E. Deverman et al.

NATURE REVIEWS DRUG DISCOVERY (2018)

Article Cell Biology

Sensitive Periods for Cerebellar-Mediated Autistic-like Behaviors

Peter T. Tsai et al.

CELL REPORTS (2018)

Article Genetics & Heredity

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Christian R. Marshall et al.

NATURE GENETICS (2017)

Review Biotechnology & Applied Microbiology

Small But Increasingly Mighty: Latest Advances in AAV Vector Research, Design, and Evolution

Dirk Grimm et al.

HUMAN GENE THERAPY (2017)

Article Biotechnology & Applied Microbiology

A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear

Lukas D. Landegger et al.

NATURE BIOTECHNOLOGY (2017)

Article Medicine, General & Internal

Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy

J. R. Mendell et al.

NEW ENGLAND JOURNAL OF MEDICINE (2017)

Article Medicine, General & Internal

Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy

R. S. Finkel et al.

NEW ENGLAND JOURNAL OF MEDICINE (2017)

Review Clinical Neurology

Intracerebroventricular Delivery as a Safe, Long-Term Route of Drug Administration

Jessica L. Cohen-Pfeffer et al.

PEDIATRIC NEUROLOGY (2017)

Article Multidisciplinary Sciences

Dosage sensitivity is a major determinant of human copy number variant pathogenicity

Alan M. Rice et al.

NATURE COMMUNICATIONS (2017)

Review Immunology

Lessons from ten years of genome-wide association studies of asthma

Cristina T. Vicente et al.

CLINICAL & TRANSLATIONAL IMMUNOLOGY (2017)

Article Clinical Neurology

Glymphatic MRI in idiopathic normal pressure hydrocephalus

Geir Ringstad et al.

BRAIN (2017)

Review Genetics & Heredity

10 Years of GWAS Discovery: Biology, Function, and Translation

Peter M. Visscher et al.

AMERICAN JOURNAL OF HUMAN GENETICS (2017)

Article Psychology, Developmental

Heritability of autism spectrum disorders: a meta-analysis of twin studies

Beata Tick et al.

JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY (2016)

Review Pharmacology & Pharmacy

CSF, blood-brain barrier, and brain drug delivery

William M. Pardridge

EXPERT OPINION ON DRUG DELIVERY (2016)

Article Biotechnology & Applied Microbiology

Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII

Brittney L. Gurda et al.

MOLECULAR THERAPY (2016)

Article Biotechnology & Applied Microbiology

Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain

Benjamin E. Deverman et al.

NATURE BIOTECHNOLOGY (2016)

Article Medicine, Research & Experimental

Functional correction of neurological and somatic disorders at later stages of disease in MPS IIIA mice by systemic scAAV9-hSGSH gene delivery

Haiyan Fu et al.

MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT (2016)

Article Medicine, Research & Experimental

AAV9-mediated central nervous system-targeted gene delivery via cisterna magna route in mice

Vera Lukashchuk et al.

MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT (2016)

Article Medicine, Research & Experimental

Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model

Sara Silva-Santos et al.

JOURNAL OF CLINICAL INVESTIGATION (2015)

Article Multidisciplinary Sciences

Towards a therapy for Angelman syndrome by targeting a long non-coding RNA

Linyan Meng et al.

NATURE (2015)

Article Multidisciplinary Sciences

Synaptic, transcriptional and chromatin genes disrupted in autism

Silvia De Rubeis et al.

NATURE (2014)

Article Genetics & Heredity

Most genetic risk for autism resides with common variation

Trent Gaugler et al.

NATURE GENETICS (2014)

Review Neurosciences

Biology of adeno-associated viral vectors in the central nervous system

Giridhar Murlidharan et al.

FRONTIERS IN MOLECULAR NEUROSCIENCE (2014)

Review Genetics & Heredity

Angelman syndrome: review of clinical and molecular aspects

Lynne M. Bird

APPLICATION OF CLINICAL GENETICS (2014)

Article Multidisciplinary Sciences

Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy

Alessandra Biffi et al.

SCIENCE (2013)

Article Biotechnology & Applied Microbiology

MicroRNA-regulated, Systemically Delivered rAAV9: A Step Closer to CNS-restricted Transgene Expression

Jun Xie et al.

MOLECULAR THERAPY (2011)

Review Psychology, Developmental

Child and adolescent psychiatric genetics

Johannes Hebebrand et al.

EUROPEAN CHILD & ADOLESCENT PSYCHIATRY (2010)

Article Biotechnology & Applied Microbiology

Intravenous Administration of Self-complementary AAV9 Enables Transgene Delivery to Adult Motor Neurons

Sandra Duque et al.

MOLECULAR THERAPY (2009)

Article Biotechnology & Applied Microbiology

Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes

Kevin D. Foust et al.

NATURE BIOTECHNOLOGY (2009)

Article Biochemistry & Molecular Biology

Molecular signatures of disease brain endothelia provide new sites for CNS-directed enzyme therapy

Yong Hong Chen et al.

NATURE MEDICINE (2009)

Review Biotechnology & Applied Microbiology

Therapeutic potential of Toll-like receptor 9 activation

Arthur M. Krieg

NATURE REVIEWS DRUG DISCOVERY (2006)

Article Physiology

Spinal CSF absorption in healthy individuals

M Edsbagge et al.

AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY (2004)