Delivering AAV to the Central Nervous and Sensory Systems.
Ontology highlight
ABSTRACT:
SUBMITTER: Peters CW
PROVIDER: S-EPMC9302199 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Adeno-associated virus (AAV) is a non-pathogenic virus that mainly infects primates with the help of adenoviruses. AAV is being widely used as a delivery vector for in vivo gene therapy, as evidenced by five currently approved drugs and more than 255 clinical trials across the world. Due to its relatively low immunogenicity and toxicity, sustained efficacy, and broad tropism, AAV holds great promise for treating many indications, including central nervous system (CNS), ocular, muscular, and liver diseases. However, low delivery efficiency, especially for the CNS due to the blood-brain barrier (BBB), remains a significant challenge for more clinical application of AAV gene therapy. Thus, there is an urgent need for utilizing AAV engineering to discover next-generation capsids with improved properties, e.g., enhanced BBB penetrance, lower immunogenicity, and higher packaging efficiency. AAV engineering methods, including directed evolution, rational design, and in silico design, have been developed, resulting in the discovery of novel capsids (e.g., PhP.B, B10, PAL1A/B/C). In this review, we discuss key studies that identified engineered CNS capsids and/or established methodological improvements. Further, we also discussed important issues that need to be addressed, including cross-species translatability, cell specificity, and modular engineering to improve multiple properties simultaneously.
| S-EPMC9953251 | biostudies-literature
Project description:Invertebrate chordates, such as the tunicate Ciona, can offer insight into the evolution of the chordate phylum. Anatomical features that are shared between invertebrate chordates and vertebrates may be taken as evidence of their presence in a common chordate ancestor. The central nervous systems of Ciona larvae and vertebrates share a similar anatomy despite the Ciona CNS having ~180 neurons. However, the depth of conservation between the Ciona CNS and those in vertebrates is not resolved. The Ciona caudal CNS, while appearing spinal cord-like, has hitherto been thought to lack motor neurons, bringing into question its homology with the vertebrate spinal cord. We show here that the Ciona larval caudal CNS does, in fact, have functional motor neurons along its length, pointing to the presence of a spinal cord-like structure at the base of the chordates. We extend our analysis of shared CNS anatomy further to explore the Ciona "motor ganglion", which has been proposed to be a homolog of the vertebrate hindbrain, spinal cord, or both. We find that a cluster of neurons in the dorsal motor ganglion shares anatomical location, developmental pathway, neural circuit architecture, and gene expression with the vertebrate cerebellum. However, functionally, the Ciona cluster appears to have more in common with vertebrate cerebellum-like structures, insofar as it receives and processes direct sensory input. These findings are consistent with earlier speculation that the cerebellum evolved from a cerebellum-like structure, and suggest that the latter structure was present in the dorsal hindbrain of a common chordate ancestor.
| S-EPMC11185728 | biostudies-literature
Project description:BACKGROUND:Neurodevelopmental disorders, as a class of diseases, have been particularly difficult to treat even when the underlying cause(s), such as genetic alterations, are understood. What treatments do exist are generally not curative and instead seek to improve quality of life for affected individuals. The advent of gene therapy via gene replacement offers the potential for transformative therapies to slow or even stop disease progression for current patients and perhaps minimize or prevent the appearance of symptoms in future patients. MAIN BODY:This review focuses on adeno-associated virus (AAV) gene therapies for diseases of the central nervous system. An overview of advances in AAV vector design for therapy is provided, along with a description of current strategies to develop AAV vectors with tailored tropism. Next, progress towards treatment of neurodegenerative diseases is presented at both the pre-clinical and clinical stages, focusing on a few select diseases to highlight broad categories of therapeutic parameters. Special considerations for more challenging cases are then discussed in addition to the immunological aspects of gene therapy. CONCLUSION:With the promising clinical trial results that have been observed for the latest AAV gene therapies and continued pre-clinical successes, the question is no longer whether a therapy can be developed for certain neurodevelopmental disorders, but rather, how quickly.
| S-EPMC5960126 | biostudies-literature
Project description:Endothelial cells have a crucial role in nervous system function, and mounting evidence points to endothelial impairment as a major contributor to a wide range of neurological diseases. However, tools to genetically interrogate these cells in vivo remain limited. Here, we describe AAV-BI30, a capsid that specifically and efficiently transduces endothelial cells throughout the central nervous system. At relatively low systemic doses, this vector transduces the majority of arterial, capillary, and venous endothelial cells in the brain, retina, and spinal cord vasculature of adult C57BL/6 mice. Furthermore, we show that AAV-BI30 robustly transduces endothelial cells in multiple mouse strains and rats in vivo and human brain microvascular endothelial cells in vitro. Finally, we demonstrate AAV-BI30's capacity to achieve efficient and endothelial-specific Cre-mediated gene manipulation in the central nervous system. This combination of attributes makes AAV-BI30 uniquely well-suited to address outstanding research questions in neurovascular biology and aid the development of therapeutics to remediate endothelial dysfunction in disease.
| S-EPMC9103166 | biostudies-literature
Project description:Central Nervous System (CNS) diseases, such as Alzheimer's diseases (AD), Parkinson's Diseases (PD), brain tumors, Huntington's disease (HD), and stroke, still remain difficult to treat by the conventional molecular drugs. In recent years, various gene therapies have come into the spotlight as versatile therapeutics providing the potential to prevent and treat these diseases. Despite the significant progress that has undoubtedly been achieved in terms of the design and modification of genetic modulators with desired potency and minimized unwanted immune responses, the efficient and safe in vivo delivery of gene therapies still poses major translational challenges. Various non-viral nanomedicines have been recently explored to circumvent this limitation. In this review, an overview of gene therapies for CNS diseases is provided and describes recent advances in the development of nanomedicines, including their unique characteristics, chemical modifications, bioconjugations, and the specific applications that those nanomedicines are harnessed to deliver gene therapies.
| S-EPMC9475540 | biostudies-literature
Project description:Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease arising from mutations in β-d-glucuronidase (GUSB), which results in glycosaminoglycan (GAG) accumulation and a variety of clinical manifestations including neurological disease. Herein, MPS VII dogs were injected intravenously (i.v.) and/or intrathecally (i.t.) via the cisterna magna with AAV9 or AAVrh10 vectors carrying the canine GUSB cDNA. Although i.v. injection alone at 3 days of age resulted in normal cerebrospinal fluid (CSF) GUSB activity, brain tissue homogenates had only ~1 to 6% normal GUSB activity and continued to have elevated GAG storage. In contrast, i.t. injection at 3 weeks of age resulted in CSF GUSB activity 44-fold normal while brain tissue homogenates had >100% normal GUSB activity and reduced GAGs compared with untreated dogs. Markers for secondary storage and inflammation were eliminated in i.t.-treated dogs and reduced in i.v.-treated dogs compared with untreated dogs. Given that i.t.-treated dogs expressed higher levels of GUSB in the CNS tissues compared to those treated i.v., we conclude that i.t. injection of AAV9 or AAVrh10 vectors is more effective than i.v. injection alone in the large animal model of MPS VII.
| S-EPMC4817811 | biostudies-literature
Project description:Adeno-associated viral (AAV) vectors have shown promise as a platform for gene therapy of neurological disorders. Achieving global gene delivery to the central nervous system (CNS) is key for development of effective therapies for many of these diseases. Here we report the isolation of a novel CNS tropic AAV capsid, AAV-B1, after a single round of in vivo selection from an AAV capsid library. Systemic injection of AAV-B1 vector in adult mice and cat resulted in widespread gene transfer throughout the CNS with transduction of multiple neuronal subpopulations. In addition, AAV-B1 transduces muscle, β-cells, pulmonary alveoli, and retinal vasculature at high efficiency. This vector is more efficient than AAV9 for gene delivery to mouse brain, spinal cord, muscle, pancreas, and lung. Together with reduced sensitivity to neutralization by antibodies in pooled human sera, the broad transduction profile of AAV-B1 represents an important improvement over AAV9 for CNS gene therapy.
| S-EPMC5088762 | biostudies-literature
Project description:A new mouse model for congenital Zika infection in a wildtype, immunocompetent background employing intraplacental infection resulted in productive infection of embryonic brains and features of microcephaly during early development (E10.5-16.5). Gross morphological characterization showed translational relevance for understanding the viral neuropathogenesis and Zika-associated microcephaly in humans. Thus, an integrated, multi-omics (RNA-sequencing, proteomics) analysis of fetal brain tissues was performed to understand pathways perturbed by viral infection in developing brains. These analyses identified virus-induced defects in cell cycle progression and neurodevelopment, in S-phase DNA replication and NEUROD2/TBR2 transcription factor cascades, respectively. Among the most significant responses was induction of innate immune programs in ZIKV-infected brains, including immunoproteasome activation and MHC-I antigen display associated with immune cell infiltration and neuronal death during early development. Identification of specific components within major pathways contributing to viral infection-induced effects on neurodevelopment provides novel targets for therapeutic intervention against neurotropic infections and ZIKV-associated microcephaly specifically.
2021-08-21 | GSE118935 | GEO
Project description:Non-human primates (NHPs) are a preferred animal model for optimizing adeno-associated virus (AAV)-mediated CNS gene delivery protocols before clinical trials. In spite of its inherent appeal, it is challenging to compare different serotypes, delivery routes, and disease indications in a well-powered, comprehensive, multigroup NHP experiment. Here, a multiplex barcode recombinant AAV (rAAV) vector-tracing strategy has been applied to a systemic analysis of 29 distinct, wild-type (WT), AAV natural isolates and engineered capsids in the CNS of eight macaques. The report describes distribution of each capsid in 15 areas of the macaques' CNS after intraparenchymal (putamen) injection, or cerebrospinal fluid (CSF)-mediated administration routes (intracisternal, intrathecal, or intracerebroventricular). To trace the vector biodistribution (viral DNA) and targeted tissues transduction (viral mRNA) of each capsid in each of the analyzed CNS areas, quantitative next-generation sequencing analysis, assisted by the digital-droplet PCR technology, was used. The report describes the most efficient AAV capsid variants targeting specific CNS areas after each route of administration using the direct side-by-side comparison of WT AAV isolates and a new generation of rationally designed capsids. The newly developed bioinformatics and visualization algorithms, applicable to the comparative analysis of several mammalian brain models, have been developed and made available in the public domain.
| S-EPMC8417503 | biostudies-literature
Project description:Certain microbes invade brain microvascular endothelial cells (BMECs) to breach the blood-brain barrier (BBB) and establish central nervous system (CNS) infection. Here we use the leading meningitis pathogen group B Streptococcus (GBS) together with insect and mammalian infection models to probe a potential role of glycosaminoglycan (GAG) interactions in the pathogenesis of CNS entry. Site-directed mutagenesis of a GAG-binding domain of the surface GBS alpha C protein impeded GBS penetration of the Drosophila BBB in vivo and diminished GBS adherence to and invasion of human BMECs in vitro. Conversely, genetic impairment of GAG expression in flies or mice reduced GBS dissemination into the brain. These complementary approaches identify a role for bacterial-GAG interactions in the pathogenesis of CNS infection. Our results also highlight how the simpler yet genetically conserved Drosophila GAG pathways can provide a model organism to screen candidate molecules that can interrupt pathogen-GAG interactions for future therapeutic applications.
| S-EPMC3121876 | biostudies-literature