Safe and effective superoxide dismutase 1 silencing using artificial microRNA in macaques

Borel, Florie; Gernoux, Gwladys; Sun, Huaming; Stock, Rachel; Blackwood, Meghan; Brown, Robert H.; Mueller, Christian

doi:10.1126/scitranslmed.aau6414

Cited by 65 publications

(56 citation statements)

References 42 publications

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“…With the recent FDA and EMA approvals for Zolgensma, Luxturna, and Glybera, recombinant AAVs (rAAVs) are now, more than ever, considered efficient and successful viral vectors for the treatment of inherited disorders. Its variety of serotypes offers a large spectrum of abilities to transduce tissues, including the liver, 1,2 muscle, [3][4][5][6] central nervous system (CNS), [7][8][9] and retina, 10,11 as demonstrated in preclinical studies targeting metabolic, [12][13][14][15][16] neuromuscular, 17-20 neurodegenerative, 21,22 and retinal [23][24][25] disorders. Interestingly, certain serotypes of AAV capsids elicit more robust immune responses than others, with AAV8 being less immunoreactive and AAVrh32.33 being more immunoreactive in mouse models.…”

Section: Introductionmentioning

confidence: 99%

Muscle-Directed Delivery of an AAV1 Vector Leads to Capsid-Specific T Cell Exhaustion in Nonhuman Primates and Humans

et al. 2020

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With the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approvals for Zolgensma, Luxturna, and Glybera, recombinant adeno-associated viruses (rAAVs) are considered efficient tools for gene transfer. However, studies in animals and humans demonstrate that intramuscular (IM) AAV delivery can trigger immune responses to AAV capsids and/or transgenes. IM delivery of rAAV1 in humans has also been described to induce tolerance to rAAV characterized by the presence of capsid-specific regulatory T cells (Tregs) in periphery. To understand mechanisms responsible for tolerance and parameters involved, we tested 3 muscledirected administration routes in rhesus monkeys: IM delivery, venous limb perfusion, and the intra-arterial push and dwell method. These 3 methods were well tolerated and led to transgene expression. Interestingly, gene transfer in muscle led to Tregs and exhausted T cell infiltrates in situ at both day 21 and day 60 post-injection. In human samples, an in-depth analysis of the functionality of these cells demonstrates that capsid-specific exhausted T cells are detected after at least 5 years post-vector delivery and that the exhaustion can be reversed by blocking the checkpoint pathway. Overall, our study shows that persisting transgene expression after gene transfer in muscle is mediated by Tregs and exhausted T cells.

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Section: Introductionmentioning

confidence: 99%

Muscle-Directed Delivery of an AAV1 Vector Leads to Capsid-Specific T Cell Exhaustion in Nonhuman Primates and Humans

et al. 2020

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“…In MPTP-induced mouse PD model, Lee et al found that genetic inactivation of NLRP3 abolishes MPTP-induced microglial activation, recruitment, and IL-1β production in the subsantia nigra of mouse brain [49]. Furthermore, pharmacological inhibition of NLRP3 inflammasome also displays potent inhibitory effects on microglial activation in 6-OHDA and α-synuclein rodent PD models [33]. Consistent with these reports, NLRP3 inflammasome activation was observed in P + M-treated mice.…”

Section: Discussionmentioning

confidence: 70%

“…Previous studies indicated that the activation of nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a key factor to regulate microglial activation in neurodegenerative diseases [32,33]. To explore whether NLRP3 inflammasome is involved in CD11bmediated microglial activation, the effects of CD11b on activation of NLRP3 inflammasome were determined in mice treated with P + M. As illustrated in Fig.…”

Section: Cd11b Deficiency Diminishes P + M-induced Nlrp3 Inflammasomementioning

confidence: 99%

Integrin CD11b mediates locus coeruleus noradrenergic neurodegeneration in a mouse Parkinson’s disease model

Hou

Qiu

et al. 2020

J Neuroinflammation

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Background: The loss of locus coeruleus noradrenergic (LC/NE) neurons in the brainstem is reported in multiple neurodegenerative disorders, including Parkinson's disease (PD). However, the mechanisms remain unclear. Strong evidence suggested that microglia-mediated neuroinflammation contributes to neurodegeneration in PD. We recently recognized integrin CD11b, the α-chain of macrophage antigen complex-1 (Mac-1, also called CR3), as a key regulator for microglial activation. However, whether CD11b is involved in LC/NE neurodegeneration in PD remains to be investigated. Methods: LC/NE neurodegeneration and microglial activation were compared between wild type (WT) and CD11b KO mice after treated with paraquat and maneb, two pesticides that widely used to create PD model. The role of NLRP3 inflammasome in CD11b-mediated microglial dysfunction and LC/NE neurodegeneration was further explored. LC/NE neurodegeneration, microglial phenotype, and NLRP3 inflammasome activation were determined by using Western blot, immunohistochemistry, and RT-PCR technologies. Results: Paraquat and maneb co-exposure elevated the expressions of CD11b in the brainstem of mice, and CD11b knockout significantly reduced LC/NE neurodegeneration induced by paraquat and maneb. Mitigated microglial activation and gene expressions of proinflammatory cytokines were also observed in paraquat and maneb-treated CD11b −/− mice. Mechanistically, CD11b-mediated NLRP3 inflammasome activation contributes to paraquat and maneb-induced LC/NE neurodegeneration. Compared with WT controls, CD11b deficiency reduced paraquat and maneb-induced NLRP3 expression, caspase-1 activation, and interleukin-1β production in mice. Furthermore, inhibition of NLRP3 inflammasome by glybenclamide, a sulfonylurea inhibitor of NLRP3 inflammasome, was found to be able to suppress microglial proinflammatory activation and nuclear factor-κB activation induced by paraquat and maneb. Moreover, reduced reactive oxygen species production, NADPH oxidase, and inducible nitric oxide synthase expressions as well as 4-hydroxynonenal and malondialdehyde levels were detected in combined glybenclamide and paraquat and maneb-treated mice compared with paraquat and maneb alone group. Finally, we found that glybenclamide treatment ameliorated LC/NE neurodegeneration and α-synuclein aggregation in paraquat and maneb-treated mice.

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“…Neuronal activity is also affect by other cell types, such as astrocytes, so the functions of miR‐3068‐3p in astrocytes are also worth investigating. Besides, Considering the therapeutic potential of miRNAs in brain damage (Borel et al, ; Kim, Mehta, & Morris‐Blanco, ) and the possibility of delivering the lentivirus or AmmTx3 to the brain by stereotactic injection, additional in vivo research is needed to validate the role of miR‐3068‐3p and kcnip4 in the damaged brain after ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

Down‐regulation of miR‐3068‐3p enhances kcnip4‐regulated A‐type potassium current to protect against glutamate‐induced excitotoxicity

Wang

Zhou

et al. 2019

Journal of Neurochemistry

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The main cause of excitotoxic neuronal death in ischemic stroke is the massive release of glutamate. Recently, microRNAs (miRNAs) have been found to play an essential role in stroke pathology, although the molecular mechanisms remain to be investigated. Here, to identify potential candidate miRNAs involved in excitotoxicity, we treated rat primary cortical neurons with glutamate and found that miR‐3068‐3p, a novel miRNA, was up‐regulated. We hypothesized that restoring miR‐3068‐3p expression might influence the neuronal injury outcomes. The inhibition of miR‐3068‐3p, using tough decoy lentiviruses, significantly attenuated the effects of glutamate on neuronal viability and intracellular calcium overload. To unravel the mechanisms, we employed bioinformatics analysis and RNA sequencing to identify downstream target genes. Additional luciferase assays and western blots validated kcnip4, a Kv4‐mediated A‐type potassium current (IA) regulator, as a direct target of miR‐3068‐3p. The inhibition of miR‐3068‐3p increased kcnip4 expression and vice versa. In addition, the knockdown of kcnip4 by shRNA abolished the protective effect of miR‐3068‐3p, and over‐expressing kcnip4 alone was sufficient to play a neuroprotective role in excitotoxicity. Moreover the inhibition of miR‐3068‐3p enhanced the IA density, and the pharmacological inhibition of IA abrogated the protective role of miR‐3068‐3p inhibition and kcnip4 over‐expression. Therefore, we conclude that inhibition of miR‐3068‐3p protects against excitotoxicity via its target gene, kcnip4, and kcnip4‐regulated IA. Our data suggest that the miR‐3068‐3p/kcnip4 axis may serve as a novel target for the treatment of ischemic stroke.

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Safe and effective superoxide dismutase 1 silencing using artificial microRNA in macaques

Cited by 65 publications

References 42 publications

Muscle-Directed Delivery of an AAV1 Vector Leads to Capsid-Specific T Cell Exhaustion in Nonhuman Primates and Humans

Muscle-Directed Delivery of an AAV1 Vector Leads to Capsid-Specific T Cell Exhaustion in Nonhuman Primates and Humans

Integrin CD11b mediates locus coeruleus noradrenergic neurodegeneration in a mouse Parkinson’s disease model

Down‐regulation of miR‐3068‐3p enhances kcnip4‐regulated A‐type potassium current to protect against glutamate‐induced excitotoxicity

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