Adeno-Associated Virus Engineering and Load Strategy for Tropism Modification, Immune Evasion and Enhanced Transgene Expression DOI Creative Commons
Xun Zhou, Jingzhou Liu, Shuang Xiao

et al.

International Journal of Nanomedicine, Journal Year: 2024, Volume and Issue: Volume 19, P. 7691 - 7708

Published: July 1, 2024

Abstract: Gene therapy aims to add, replace or turn off genes help treat disease. To date, the US Food and Drug Administration (FDA) has approved 14 gene products. With increasing interest in therapy, feasible delivery vectors are necessary for inserting new into cells. There different kinds of including viral like lentivirus, adenovirus, retrovirus, adeno-associated virus et al, non-viral naked DNA, lipid vectors, polymer nanoparticles, exosomes with viruses being most commonly used. Among them, concerned vector is (AAV) because its safety, natural ability efficiently deliver cells sustained transgene expression multiple tissues. In addition, AAV genome can be engineered generate recombinant (rAAV) containing sequences been proven a safe vector. Recently, rAAV have treatment various rare diseases. Despite these approvals, some major limitations remain, namely nonspecific tissue targeting host immune response. Additional problems include neutralizing antibodies that block delivery, finite packaging capacity, high titer used per dose cost. deal challenges, several techniques developed. Based on differences engineering methods, this review proposes three strategies: engineering-based capsid modification (capsid modification), surface tethering through chemical conjugation (surface tethering), other formulations loaded (virus load). advantages encountered strategies summarized. Keywords: engineering, modification, tethering, load, rational design, directed evolution, machine learning

Language: Английский

The microglial innate immune protein PGLYRP1 mediates neuroinflammation and consequent behavioral changes DOI Creative Commons

Anup Bhusal,

Jae‐Hong Kim, Seung-Chan Kim

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(3), P. 113813 - 113813

Published: Feb. 22, 2024

Peptidoglycan recognition protein 1 (PGLYRP1) is a pattern-recognition that mediates antibacterial actions and innate immune responses. Its expression role in neuroinflammatory conditions remain unclear. We observed the upregulation of PGLYRP1 inflamed human mouse spinal cord brain, with microglia being primary cellular source. Experiments using recombinant show potentiates reactive gliosis, neuroinflammation, consequent behavioral changes multiple animal models neuroinflammation. Furthermore, shRNA-mediated knockdown Pglyrp1 gene attenuates this inflammatory response. In addition, we identify triggering receptor expressed on myeloid cell-1 (TREM1) as an interaction partner demonstrate promotes neuroinflammation through TREM1-Syk-Erk1/2-Stat3 axis cultured glial cells. Taken together, our results reveal for microglial mediator. Finally, propose potential biomarker therapeutic target various diseases.

Language: Английский

Citations

13
Microglia in Health and Diseases: Integrative Hubs of the Central Nervous System (CNS) DOI
Amanda Sierra, Véronique E. Miron, Rosa Chiara Paolicelli

et al.

Cold Spring Harbor Perspectives in Biology, Journal Year: 2024, Volume and Issue: 16(8), P. a041366 - a041366

Published: March 4, 2024

Amanda Sierra1,2,3, Veronique E. Miron4,5,6, Rosa C. Paolicelli7 and Richard M. Ransohoff8 1Achucarro Basque Center for Neuroscience, Glial Cell Biology Laboratory, Science Park of UPV/EHU, E-48940 Leioa, Bizkaia, Spain 2Department Biochemistry Molecular Biology, University the Country EHU/UPV, 48940 3Ikerbasque Foundation, Bilbao 48009, 4BARLO Multiple Sclerosis Centre, Keenan Research Centre Biomedical at St. Michael's Hospital, Toronto M5B 1T8, Canada 5Department Immunology, Toronto, M5S 1A8, 6UK Dementia Institute Edinburgh, Edinburgh BioQuarter, EH16 4TJ, United Kingdom 7Department Sciences, Faculty Medicine, Lausanne, CH-1005 Switzerland 8Third Rock Ventures, Boston, Massachusetts 02215, USA Correspondence: amanda.sierra{at}achucarro.org; rransohoff{at}thirdrockventures.com

Language: Английский

Citations

13
Arresting the bad seed: HDAC3 regulates proliferation of different microglia after ischemic stroke DOI Creative Commons
Yue Zhang, Jiaying Li, Yongfang Zhao

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(10)

Published: March 6, 2024

The accumulation of self-renewed polarized microglia in the penumbra is a critical neuroinflammatory process after ischemic stroke, leading to secondary demyelination and neuronal loss. Although known regulate tumor cell proliferation neuroinflammation, HDAC3's role microgliosis microglial polarization remains unclear. We demonstrated that HDAC3 knockout (HDAC3-miKO) ameliorated poststroke long-term functional histological outcomes. RNA-seq analysis revealed mitosis as primary affected HDAC3-deficent following stroke. Notably, HDAC3-miKO specifically inhibited proinflammatory without affecting anti-inflammatory microglia, preventing transition state. Moreover, ATAC-seq showed induced closing accessible regions enriched with PU.1 motifs. Overexpressing via an AAV approach reversed HDAC3-miKO-induced inhibition protective effects on indicating downstream molecule mediates These findings uncovered HDAC3/PU.1 axis, which mediated differential proliferation-related reprogramming different populations, drove inflammatory state transition, contributed pathophysiology

Language: Английский

Citations

13
Microglia: Activity‐dependent regulators of neural circuits DOI

Violeta Durán Laforet,

Dorothy P. Schafer

Annals of the New York Academy of Sciences, Journal Year: 2024, Volume and Issue: 1533(1), P. 38 - 50

Published: Jan. 31, 2024

Abstract It has been more than a century since Pío del Río‐Hortega first characterized microglia in histological stains of brain tissue. Since then, significant advances have made understanding the role these resident central nervous system (CNS) macrophages. In particular, it is now known that can sense neural activity and modulate neuronal circuits accordingly. We review mechanisms by which detect changes to then synapse numbers developing mature CNS. This includes responses both spontaneous experience‐driven activity. further discuss activity‐dependent regulate synaptic function circuit excitability. Together, our discussion provides comprehensive functions within healthy CNS, highlights exciting new open questions related fully as key components regulators circuits.

Language: Английский

Citations

12
SELENOK-dependent CD36 palmitoylation regulates microglial functions and Aβ phagocytosis DOI Creative Commons

Pei Ouyang,

Zhiyu Cai,

Jiaying Peng

et al.

Redox Biology, Journal Year: 2024, Volume and Issue: 70, P. 103064 - 103064

Published: Feb. 2, 2024

Amyloid-beta (Aβ) is a key factor in the onset and progression of Alzheimer's disease (AD). Selenium (Se) compounds show promise AD treatment. Here, we revealed that selenoprotein K (SELENOK), involved immune regulation potentially related to pathology, plays critical role microglial response, migration, phagocytosis. In vivo vitro studies corroborated SELENOK deficiency inhibits Aβ phagocytosis, exacerbating cognitive deficits 5xFAD mice, which are reversed by overexpression. Mechanistically, CD36 palmitoylation through DHHC6, regulating localization plasma membranes thus impacting was reduced brains patients mice with AD. Se supplementation promoted expression palmitoylation, enhancing phagocytosis mitigating progression. We have identified regulatory mechanisms from Se-dependent selenoproteins providing novel insights into potential therapeutic strategies involving selenoproteins.

Language: Английский

Citations

10
Microglial activation and polarization in type 2 diabetes-related cognitive impairment: A focused review of pathogenesis DOI Creative Commons

Yue Tian,

Guangchan Jing,

Mei Ma

et al.

Neuroscience & Biobehavioral Reviews, Journal Year: 2024, Volume and Issue: 165, P. 105848 - 105848

Published: Aug. 13, 2024

Microglia, as immune cells in the central nervous system, are closely related to cognitive impairment associated with type 2 diabetes (T2D). Preliminary explorations have investigated relationship between T2D-related and activation polarization of microglia. This review summarizes potential mechanisms microglial context T2D. It discusses inflammatory responses, neuronal apoptosis, amyloid-β deposition, abnormal phosphorylation Tau protein mediated by polarization, exploring connections from multiple perspectives. Additionally, this provides references for future treatment targeting microglia clinical translation.

Language: Английский

Citations

9
Development of microglia-targeting adeno-associated viral vectors as tools to study microglial behavior in vivo DOI Creative Commons

Yukihiro Okada,

Nobutake Hosoi, Yasunori Matsuzaki

et al.

Communications Biology, Journal Year: 2022, Volume and Issue: 5(1)

Published: Nov. 11, 2022

Abstract Here we describe the microglia-targeting adeno-associated viral (AAV) vectors containing a 1.7-kb putative promoter region of microglia/macrophage-specific ionized calcium-binding adaptor molecule 1 ( Iba1 ), along with repeated miRNA target sites for microRNA (miR)-9 and miR-129-2-3p. The genomic sequence upstream start codon in exon Aif1 ) gene, functions as microglia preferential striatum cerebellum. Furthermore, ectopic transgene expression non-microglial cells is markedly suppressed upon adding two sets 4-repeated miR-9 miR-129-2-3p, which are expressed exclusively sponged AAV-derived mRNAs. Our transduced ramified healthy tissues reactive lipopolysaccharide-treated mice mouse model neurodegenerative disease. Moreover, live fluorescent imaging allowed monitoring microglial motility intracellular Ca 2+ mobilization. Thus, AAV valuable studying pathophysiology therapies, particularly

Language: Английский

Citations

29
Chemogenetic modulation of astrocytes and microglia: State‐of‐the‐art and implications in neuroscience DOI Creative Commons
Jo Bossuyt, Yana Van Den Herrewegen, Liam Nestor

et al.

Glia, Journal Year: 2023, Volume and Issue: 71(9), P. 2071 - 2095

Published: May 24, 2023

Insights into the role astrocytes and microglia play in normal diseased brain functioning has expanded drastically over last decade. Recently, chemogenetic tools have emerged as cutting-edge techniques, allowing targeted spatiotemporal precise manipulation of a specific glial cell type. As result, significant advances astrocyte microglial function been made, showing how cells can intervene central nervous system (CNS) functions such cognition, reward feeding behavior addition to their established contribution diseases, pain, CNS inflammation. Here, we discuss latest insights health disease that made through application chemogenetics. We will focus on intracellular signaling pathways induced by activation designer receptors exclusively activated drugs (DREADDs) microglia. also elaborate some potential pitfalls translational DREADD technology.

Language: Английский

Citations

21
High-titer AAV disrupts cerebrovascular integrity and induces lymphocyte infiltration in adult mouse brain DOI Creative Commons

Yaowei Guo,

Junliang Chen,

Wenyu Ji

et al.

Molecular Therapy — Methods & Clinical Development, Journal Year: 2023, Volume and Issue: 31, P. 101102 - 101102

Published: Aug. 29, 2023

The brain is often described as an "immune-privileged" organ due to the presence of blood-brain-barrier (BBB), which limits entry immune cells. In general, intracranial injection adeno-associated virus (AAV) considered a relatively safe procedure. this study, we discovered that AAV, popular engineered viral vector for gene therapy, can disrupt BBB and induce cell infiltration in titer-dependent manner. First, our bulk RNA sequencing data revealed high-titer AAV significantly upregulated many genes involved disrupting integrity antiviral adaptive responses. By using histologic analysis, further demonstrated biological structure was severely disrupted adult mouse brain. Meanwhile, noticed abnormal leakage blood components, including cells, within parenchyma injected areas. Moreover, identified majority infiltrated cells were cytotoxic T lymphocytes (CTLs), resulted massive loss neurons at site injection. addition, antagonizing CTL function by administering antibodies reduced neuronal toxicity induced AAV. Collectively, findings underscore potential severe side effects might compromise proper interpretation if unaware of.

Language: Английский

Citations

20
Targeted evolution of adeno-associated virus capsids for systemic transgene delivery to microglia and tissue-resident macrophages DOI Creative Commons

Adam M. H. Young,

Bjoern Neumann,

Michael Segel

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(35)

Published: Aug. 21, 2023

Tissue macrophages, including microglia, are notoriously resistant to genetic manipulation. Here, we report the creation of Adeno-associated viruses (AAV) variants that efficiently and widely transduce microglia tissue macrophages in vivo following intravenous delivery, with transgene expression up 80%. We use this technology demonstrate manipulation gene microglial ablation, thereby providing invaluable research tools for study these important cells.

Language: Английский

Citations

17