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

AAV-based in vivo gene therapy for neurological disorders DOI
Qinglan Ling, Jessica A. Herstine, Allison M. Bradbury

et al.

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(10), P. 789 - 806

Published: Sept. 1, 2023

Language: Английский

Citations

89
A comparative analysis of microglial inducible Cre lines DOI Creative Commons
Travis E. Faust, Philip A. Feinberg, Christopher M. O’Connor

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(9), P. 113031 - 113031

Published: Aug. 26, 2023

Cre/loxP technology has revolutionized genetic studies and allowed for spatial temporal control of gene expression in specific cell types. Microglial biology particularly benefited because microglia historically have been difficult to transduce with virus or electroporation methods delivery. Here, we investigate five the most widely available microglial inducible Cre lines. We demonstrate varying degrees recombination efficiency, cell-type specificity, spontaneous recombination, depending on line inter-loxP distance. also establish best practice guidelines protocols measure microglia. There is increasing evidence that are key regulators neural circuits major drivers a broad range neurological diseases. Reliable manipulation their function vivo utmost importance. Identifying caveats benefits all tools implementing rigorous crucial growth field development microglia-based therapeutics.

Language: Английский

Citations

46
Optimal trade-off control in machine learning–based library design, with application to adeno-associated virus (AAV) for gene therapy DOI Creative Commons
Danqing Zhu, David H. Brookes, Akosua Busia

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(4)

Published: Jan. 24, 2024

Adeno-associated viruses (AAVs) hold tremendous promise as delivery vectors for gene therapies. AAVs have been successfully engineered—for instance, more efficient and/or cell-specific to numerous tissues—by creating large, diverse starting libraries and selecting desired properties. However, these often contain a high proportion of variants unable assemble or package their genomes, prerequisite any goal. Here, we present showcase machine learning (ML) method designing AAV peptide insertion that achieve fivefold higher packaging fitness than the standard NNK library with negligible reduction in diversity. To demonstrate our ML-designed library’s utility downstream engineering goals, show it yields approximately 10-fold successful after selection infection human brain tissue, leading promising glial-specific variant. Moreover, design approach can be applied other types beyond.

Language: Английский

Citations

27
Microglial P2Y6 calcium signaling promotes phagocytosis and shapes neuroimmune responses in epileptogenesis DOI
Anthony D. Umpierre, Bohan Li, Katayoun Ayasoufi

et al.

Neuron, Journal Year: 2024, Volume and Issue: 112(12), P. 1959 - 1977.e10

Published: April 12, 2024

Language: Английский

Citations

21
Microglial CMPK2 promotes neuroinflammation and brain injury after ischemic stroke DOI Creative Commons
Xin‐Yuan Guan,

Sitong Zhu,

Jin‐Qian Song

et al.

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(5), P. 101522 - 101522

Published: May 1, 2024

Neuroinflammation plays a significant role in ischemic injury, which can be promoted by oxidized mitochondrial DNA (Ox-mtDNA). Cytidine/uridine monophosphate kinase 2 (CMPK2) regulates mtDNA replication, but its neuroinflammation and injury remains unknown. Here, we report that CMPK2 expression is upregulated monocytes/macrophages microglia post-stroke humans mice, respectively. Microglia/macrophage knockdown using the Cre recombination-dependent adeno-associated virus suppresses inflammatory responses brain, reduces infarcts, improves neurological outcomes CX3CR1Cre/ERT2 mice. Mechanistically, limits newly synthesized Ox-mtDNA formation subsequently blocks NLRP3 inflammasome activation microglia/macrophages. Nordihydroguaiaretic acid (NDGA), as inhibitor, discovered to reduce mice prevent primary human monocytes from patients. Thus, these findings identify promising therapeutic target for stroke other brain disorders associated with neuroinflammation.

Language: Английский

Citations

21
Microglia as integrators of brain-associated molecular patterns DOI
Caroline C. Escoubas, Anna V. Molofsky

Trends in Immunology, Journal Year: 2024, Volume and Issue: 45(5), P. 358 - 370

Published: April 23, 2024

Language: Английский

Citations

17
The immunological perspective of major depressive disorder: unveiling the interactions between central and peripheral immune mechanisms DOI Creative Commons
Jiao Wang, Jiayi Lin,

Yanfang Deng

et al.

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Jan. 19, 2025

Major depressive disorder is a prevalent mental disorder, yet its pathogenesis remains poorly understood. Accumulating evidence implicates dysregulated immune mechanisms as key contributors to disorders. This review elucidates the complex interplay between peripheral and central components underlying pathology. Peripherally, systemic inflammation, gut dysregulation, dysfunction in organs including gut, liver, spleen adipose tissue influence brain function through neural molecular pathways. Within nervous system, aberrant microglial astrocytes activation, cytokine imbalances, compromised blood-brain barrier integrity propagate neuroinflammation, disrupting neurotransmission, impairing neuroplasticity, promoting neuronal injury. The crosstalk immunity creates vicious cycle exacerbating neuropathology. Unraveling these multifaceted immune-mediated provides insights into major disorder's pathogenic basis potential biomarkers targets. Modulating both responses represent promising multidimensional therapeutic strategy.

Language: Английский

Citations

5
The neuroimmune connectome in health and disease DOI
Michael A. Wheeler, Francisco J. Quintana

Nature, Journal Year: 2025, Volume and Issue: 638(8050), P. 333 - 342

Published: Feb. 12, 2025

Language: Английский

Citations

3
AAV Engineering for Improving Tropism to the Central Nervous System DOI Creative Commons
Muhammad S Ghauri, Li Ou

Biology, Journal Year: 2023, Volume and Issue: 12(2), P. 186 - 186

Published: Jan. 26, 2023

Adeno-associated virus (AAV) is a non-pathogenic that mainly infects primates with the help of adenoviruses. AAV being widely used as delivery vector for in vivo gene therapy, evidenced by five currently approved drugs and more than 255 clinical trials across world. Due to its relatively low immunogenicity toxicity, sustained efficacy, broad tropism, holds great promise treating many indications, including central nervous system (CNS), ocular, muscular, liver diseases. However, efficiency, especially CNS due blood-brain barrier (BBB), remains significant challenge application therapy. Thus, there an urgent need utilizing engineering discover next-generation capsids improved properties, e.g., enhanced BBB penetrance, lower immunogenicity, higher packaging efficiency. methods, directed evolution, rational design, silico have been developed, resulting discovery novel (e.g., PhP.B, B10, PAL1A/B/C). In this review, we discuss key studies identified engineered and/or established methodological improvements. Further, also discussed important issues be addressed, cross-species translatability, cell specificity, modular improve multiple properties simultaneously.

Language: Английский

Citations

31
Clearance of β-amyloid and synapses by the optogenetic depolarization of microglia is complement selective DOI Creative Commons

Zezhong Lv,

Lixi Chen,

Ping Chen

et al.

Neuron, Journal Year: 2024, Volume and Issue: 112(5), P. 740 - 754.e7

Published: Jan. 30, 2024

Language: Английский

Citations

14