Brain Targeting and Toxicological Assessment of the Extracellular Vesicle-Packaged Antioxidant Catalase-SKL Following Intranasal Administration in Mice

Hayes, Sarah H.; Liu, Qingfan; Selvakumaran, Sureka; Haney, Matthew J.; Batrakova, Elena V.; Allman, Brian L.; Walton, Paul A.; Kiser, Patti; Whitehead, Shawn N.

doi:10.1007/s12640-021-00390-6

Cited by 12 publications

(8 citation statements)

References 36 publications

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“…No significant increases in cytokine levels were found following the administration of EV-GDNF. This is consistent with our previous reports, which indicated no significant toxicity of EVs [ 54 ]. Furthermore, no total weight loss was detected in mice treated with EV-GDNF or sham EVs compared to those treated with saline ( Supplementary Figure S9 ).…”

Section: Resultssupporting

confidence: 94%

Using Extracellular Vesicles Released by GDNF-Transfected Macrophages for Therapy of Parkinson Disease

Zhao

Haney

Fallon

et al. 2022

Cells

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Extracellular vesicles (EVs) are cell-derived nanoparticles that facilitate transport of proteins, lipids, and genetic material, playing important roles in intracellular communication. They have remarkable potential as non-toxic and non-immunogenic nanocarriers for drug delivery to unreachable organs and tissues, in particular, the central nervous system (CNS). Herein, we developed a novel platform based on macrophage-derived EVs to treat Parkinson disease (PD). Specifically, we evaluated the therapeutic potential of EVs secreted by autologous macrophages that were transfected ex vivo to express glial-cell-line-derived neurotrophic factor (GDNF). EV-GDNF were collected from conditioned media of GDNF-transfected macrophages and characterized for GDNF content, size, charge, and expression of EV-specific proteins. The data revealed that, along with the encoded neurotrophic factor, EVs released by pre-transfected macrophages carry GDNF-encoding DNA. Four-month-old transgenic Parkin Q311(X)A mice were treated with EV-GDNF via intranasal administration, and the effect of this therapeutic intervention on locomotor functions was assessed over a year. Significant improvements in mobility, increases in neuronal survival, and decreases in neuroinflammation were found in PD mice treated with EV-GDNF. No offsite toxicity caused by EV-GDNF administration was detected. Overall, an EV-based approach can provide a versatile and potent therapeutic intervention for PD.

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Section: Resultssupporting

confidence: 94%

Using Extracellular Vesicles Released by GDNF-Transfected Macrophages for Therapy of Parkinson Disease

Zhao

Haney

Fallon

et al. 2022

Cells

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“…No significant increases in cytokine levels were found followed administration of EV-GDNF. This is consistent with our previous reports indicated no significant toxicity of EVs [54]. Furthermore, no total weight loss was detected in mice treated with EV-GDNF, or sham EVs compared to those treated with saline (Supplementary Figure S6).…”

Section: Neuroprotective and Anti-inflammatory Effects In Parkinq311(...supporting

confidence: 92%

Using Extracellular Vesicles Released by GDNF-transfected Macrophages for Therapy of Parkinson’s Disease

Zhao

Haney

Fallon

et al. 2022

Preprint

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Extracellular vesicles (EVs) are cell-derived nanoparticles that facilitate transport of proteins, lipids and genetic material playing important roles in intracellular communication. They have a remarkable potential as non-toxic and non-immunogenic nanocarriers for drug delivery to unreachable organs and tissues, in particular, the central nervous system (CNS). Herein, we developed a novel platform based on macrophage derived EVs to treat Parkinson’s disease (PD). Specifically, we evaluated the therapeutic potential of EVs secreted by autologous macrophages that were transfected ex vivo to express glial cell line-derived neurotrophic factor (GDNF). EV-GDNF were collected from conditioned media of GDNF-transfected macrophages and characterized for GDNF content, size, charge, and expression of EV-specific proteins. The data revealed that along with the encoded neurotrophic factor, EVs released by pre-transfected macrophages carry GDNF-encoding DNA. Four months-old transgenic Parkin Q311(X)A mice were treated with EV-GDNF via intranasal administration, and the effect of this therapeutic intervention on locomotor functions was assessed over a year. Significant improvements in mobility, increase in neuronal survival, and decrease in neuroinflammation were found in PD mice treated with EV-GDNF. No offsite toxicity caused by EV-GDNF administrations was detected. Overall, EV-based approach can provide a versatile and potent therapeutic intervention for PD.

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“…Previously, studies of intranasally administered recombinant vesicular stomatitis viral vectors (Johnson et al., 2007) and a nanogel pneumococcal vaccine formulation (Fukuyama et al., 2015) in macaques found no brain uptake. Certainly, numerous studies report that IN EVs or their presumed cargo enter the brain parenchyma (see, for example (Hayes et al., 2021; Hu et al., 2018; Pathipati et al., 2021; Thomi et al., 2019; Upadhya et al., 2020; Zhuang et al., 2011)). As a result, intranasal delivery of EVs is thought to be a promising way to treat central nervous system (CNS) disease (reviewed in (Pauwels et al., 2021)).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and biodistribution of extracellular vesicles administered intravenously and intranasally to Macaca nemestrina

Driedonks

Jiang

Carlson

et al. 2022

J of Extracellular Bio

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Extracellular vesicles (EVs) have potential in disease treatment since they can be loaded with therapeutic molecules and engineered for retention by specific tissues. However, questions remain on optimal dosing, administration and pharmacokinetics. Previous studies have addressed biodistribution and pharmacokinetics in rodents, but little evidence is available for larger animals. Here, we investigated the pharmacokinetics and biodistribution of Expi293F-derived EVs labelled with a highly sensitive nanoluciferase reporter (palmGRET) in a non-human primate model (Macaca nemestrina), comparing intravenous (IV) and intranasal (IN) administration over a 125-fold dose range. We report that EVs administered IV had longer circulation times in plasma than previously reported in mice and were detectable in cerebrospinal fluid after 30-60 min. EV association with peripheral blood mononuclear cells, especially B-cells, was observed as early as 1-min post-administration. EVs were detected in liver and spleen within 1 h of IV administration. However, IN delivery was minimal, suggesting that pretreatment approaches may be needed in large animals. Furthermore, EV circulation times strongly decreased after repeated IV administration, possibly due to immune responses and with clear implications for xenogeneic EV-based therapeutics. We hope that our findings from this baseline study in macaques will help to inform future research and therapeutic development of EVs.Tom Driedonks and Linglei Jiang contributed equally to this study.

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Brain Targeting and Toxicological Assessment of the Extracellular Vesicle-Packaged Antioxidant Catalase-SKL Following Intranasal Administration in Mice

Cited by 12 publications

References 36 publications

Using Extracellular Vesicles Released by GDNF-Transfected Macrophages for Therapy of Parkinson Disease

Using Extracellular Vesicles Released by GDNF-Transfected Macrophages for Therapy of Parkinson Disease

Using Extracellular Vesicles Released by GDNF-transfected Macrophages for Therapy of Parkinson’s Disease

Pharmacokinetics and biodistribution of extracellular vesicles administered intravenously and intranasally to Macaca nemestrina

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