Exosome-mediated delivery of antisense oligonucleotides targeting α-synuclein ameliorates the pathology in a mouse model of Parkinson's disease

Yang, Jiaolong; Luo, Shilin; Zhang, Jichun; Yu, Ting; Fu, Zhihui; Yang, Zheng; Xu, Ximing; Liu, Chaoyang; Fan, Mingxia; Zhang, Zhentao

doi:10.1016/j.nbd.2020.105218

Cited by 88 publications

(67 citation statements)

References 34 publications

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“…Blood-derived exosomes from healthy volunteers attenuated dopaminergic neuronal damage in the substantia nigra and striatum of PD mice, resulting in improved motor coordination (Sun et al, 2020 ). Intracerebroventricular injection of exosomes loaded with antisense oligonucleotides (ASO)-4 into PD mice significantly ameliorated α-syn aggregation while attenuating the degeneration of dopaminergic neurons, resulting in significant improvements in motor function (Yang et al, 2021 ) ( Figure 1C ).…”

Section: Exosomes and Parkinson's Diseasementioning

confidence: 99%

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Role of Exosomes in Brain Diseases

Zhang

Chen

et al. 2021

Front. Cell. Neurosci.

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Exosomes are a subset of extracellular vesicles that act as messengers to facilitate communication between cells. Non-coding RNAs, proteins, lipids, and microRNAs are delivered by the exosomes to target molecules (such as proteins, mRNAs, or DNA) of host cells, thereby playing a key role in the maintenance of normal brain function. However, exosomes are also involved in the occurrence, prognosis, and clinical treatment of brain diseases, such as Alzheimer's disease, Parkinson's disease, stroke, and traumatic brain injury. In this review, we have summarized novel findings that elucidate the role of exosomes in the occurrence, prognosis, and treatment of brain diseases.

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Section: Exosomes and Parkinson's Diseasementioning

confidence: 99%

“…Some new findings demonstrate that exosomes may be beneficial in the treatment of PD (Sun et al, 2020 ; Yang et al, 2021 ). Some researchers have designed shRNA minicircles to treat PD (Li et al, 2020a ).…”

Section: Exosomes and Parkinson's Diseasementioning

confidence: 99%

Role of Exosomes in Brain Diseases

Zhang

Chen

et al. 2021

Front. Cell. Neurosci.

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“…Before reaching their target site in the cells, oligonucleotides need to face several hurdles, such as the risk of RNase-mediated degradation and endosomal entrapment [ 51 ]. With the recent advances in novel delivery technologies for oligonucleotides, namely exosomes [ 52 ] (for a review see [ 53 ]) and adeno-associated viral vectors [ 54 ], two technologies have emerged with proven clinical results to overcome the delivery challenges of oligos: N-acetylgalactosamine-conjugates (GalNAc) and the use of lipid-nanoparticles (LNPs) (discussed below). A significant portion of oligonucleotide therapeutics currently in clinical trials uses one of these delivery modalities and targets liver diseases or genes mainly expressed in liver hepatocytes.…”

Section: Enabling Technologies For Oligonucleotide Therapeuticsmentioning

confidence: 99%

From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies

Adachi

Hengesbach

et al. 2021

Biomedicines

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Therapeutic oligonucleotides interact with a target RNA via Watson-Crick complementarity, affecting RNA-processing reactions such as mRNA degradation, pre-mRNA splicing, or mRNA translation. Since they were proposed decades ago, several have been approved for clinical use to correct genetic mutations. Three types of mechanisms of action (MoA) have emerged: RNase H-dependent degradation of mRNA directed by short chimeric antisense oligonucleotides (gapmers), correction of splicing defects via splice-modulation oligonucleotides, and interference of gene expression via short interfering RNAs (siRNAs). These antisense-based mechanisms can tackle several genetic disorders in a gene-specific manner, primarily by gene downregulation (gapmers and siRNAs) or splicing defects correction (exon-skipping oligos). Still, the challenge remains for the repair at the single-nucleotide level. The emerging field of epitranscriptomics and RNA modifications shows the enormous possibilities for recoding the transcriptome and repairing genetic mutations with high specificity while harnessing endogenously expressed RNA processing machinery. Some of these techniques have been proposed as alternatives to CRISPR-based technologies, where the exogenous gene-editing machinery needs to be delivered and expressed in the human cells to generate permanent (DNA) changes with unknown consequences. Here, we review the current FDA-approved antisense MoA (emphasizing some enabling technologies that contributed to their success) and three novel modalities based on post-transcriptional RNA modifications with therapeutic potential, including ADAR (Adenosine deaminases acting on RNA)-mediated RNA editing, targeted pseudouridylation, and 2′-O-methylation.

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“…The abundant cargo contained in exosomes originates from cells and surely is influenced by disease situation and, collectively, provides enough targets for testing, which reiterates the potential of exosomes as clinical biomarkers. Inherently, exosomes are nanosized vesicles naturally secreted by cells, uptaken by cells, capable of crossing the blood-brain barrier, and further exhibit immune-privileged status that can efficiently decrease drug clearance, which together makes exosomes ideal for delivering drugs for CNS diseases [100,103]. Furthermore, a number of studies have uncovered the protective effect and possible therapeutic application of exosomes in AD or PD [5][6][7].…”

Section: Conclusion and Perspectives Sectionmentioning

confidence: 99%

Central Nervous System Cell‐Derived Exosomes in Neurodegenerative Diseases

Tian

et al. 2021

Oxidative Medicine and Cellular Longevity

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Exosomes are a type of extracellular vesicles secreted by almost all kinds of mammalian cells that shuttle “cargo” from one cell to another, indicative of its role in cell-to-cell transportation. Interestingly, exosomes are known to undergo alterations or serve as a pathway in multiple diseases, including neurodegenerative diseases. In the central nervous system (CNS), exosomes originating from neurons or glia cells contribute to or inhibit the progression of CNS-related diseases in special ways. In lieu of this, the current study investigated the effect of CNS cell-derived exosomes on different neurodegenerative diseases.

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Exosome-mediated delivery of antisense oligonucleotides targeting α-synuclein ameliorates the pathology in a mouse model of Parkinson's disease

Cited by 88 publications

References 34 publications

Role of Exosomes in Brain Diseases

Role of Exosomes in Brain Diseases

From Antisense RNA to RNA Modification: Therapeutic Potential of RNA-Based Technologies

Central Nervous System Cell‐Derived Exosomes in Neurodegenerative Diseases

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