Extracellular vesicles: The next generation in gene therapy delivery

Cecchin, Riccardo; Troyer, Zach; Witwer, Ken; Morris, Kevin V.

doi:10.1016/j.ymthe.2023.01.021

Cited by 60 publications

(48 citation statements)

References 53 publications

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“…67 Loading drug payloads, such as RNAs or proteins, into EVs has attracted attention owing to the high tissue selectivity and biocompatibility. 68 In clinical trials, EVs are employed as biomarkers and active pharmaceutical ingredients based on their original functions and as drug delivery carriers. 69 We briefly summarized the recent preclinical and clinical stages of EVs based on publicly available information from each company's Web site (Table 4).…”

Section: Extracellular Vesicles As Delivery Carriersmentioning

confidence: 99%

Differences and Similarities of the Intravenously Administered Lipid Nanoparticles in Three Clinical Trials: Potential Linkage between Lipid Nanoparticles and Extracellular Vesicles

Suzuki,

Katsurada,

Hyodo

2023

Mol. Pharmaceutics

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Lipid nanoparticles (LNPs) are clinically validated drug-delivery carriers. However, clinical data on intravenously administered LNPs are limited compared with those on intramuscularly administered LNPs (mRNA vaccines against COVID-19). Here, we reviewed three clinically tested intravenously administered LNPs (patisiran, mRNA-1944, and NTLA-2001). We summarize the differences and similarities in their formulations, mechanisms of action, and pharmacokinetics profiles. In humans, patisiran and mRNA-1944 exhibited similar multiphasic pharmacokinetic profiles with a secondary peak in the RNA concentration. siRNA (patisiran) and mRNA (mRNA-1944) exhibited prolonged blood circulation and were detectable for more than 28 days after a single administration. We further summarize the basics of extracellular vesicles (EVs) and discuss the potential linkages between LNPs and EVs. This Review provides an understanding of the human clinical data of intravenous LNP formulations, which can be potentially explored to develop next-generation LNP-and EV-based drug delivery carriers.

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Section: Extracellular Vesicles As Delivery Carriersmentioning

confidence: 99%

Differences and Similarities of the Intravenously Administered Lipid Nanoparticles in Three Clinical Trials: Potential Linkage between Lipid Nanoparticles and Extracellular Vesicles

Suzuki,

Katsurada,

Hyodo

2023

Mol. Pharmaceutics

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“…The EV-rich fractions were F7-F10 and EV-Poor fractions were F15-30. Pooled fractions (7-10) and (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) were then concentrated using 10 kDa cutoff filters (Amicon Ultra-15, Millipore). Each fraction was subjected to protein concentration measurement, Nanoparticle Tracking Analysis (NTA) and western blot analysis following manufacturer's instructions.…”

Section: Size Exclusion Chromatography (Sec)mentioning

confidence: 99%

“…As EVs carry a diverse range of molecular cargo, they can serve as important biosignatures for disease diagnosis and therapeutic intervention. The potential diagnostic 21 and therapeutic application 22 of EVs highlights the importance for developing new protocols for their rapid isolation with purity to enable continued laboratory investigations and development as a valuable tool in disease management. However, the production of EVs, especially at an industrial scale, still represents a significant challenge, including product definition, low purity, and low yields [23][24][25] .…”

Section: Introductionmentioning

confidence: 99%

Rapid and high yield isolation of extracellular vesicles with purity by application of size exclusion fast performance liquid chromatography

Kapoor,

Harris,

Arian

et al. 2023

Preprint

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Extracellular Vesicles (EVs) have emerged as potential biomarkers for diagnosing a range of diseases without invasive procedures. Extracellular vesicles also offer an advantage compared to synthetic vesicles, for delivery of various drugs. However, limitations in segregating EVs from soluble proteins have led to inconsistent EV retrieval rates with low levels of purity. Here, we report a new high-yield (>95%) and rapid (<20 min) EV isolation method called Size Exclusion Fast Performance Liquid Chromatography (SE FPLC). We show SE FPLC can effectively isolate EVs from multiple sources including EVs derived from human and mouse cells and serum. The results indicate that SE FPLC can successfully remove highly abundant protein contaminants such as albumin and lipoprotein complexes, which can represent a major hurdle in large scale isolation of EVs for clinical translation. Additionally, the high-yield nature of SE FPLC allows for easy industrial upscaling of extracellular vesicles production for various clinical utilities. Moreover, SE FPLC enables analysis of very small volumes of blood for use in point-of-care diagnostics in the clinic. Collectively, SE FPLC offers many advantages over current EV isolation methods and offers rapid clinical utility potential.

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“…Some of the proposed functions of RNAs transferred to recipient cells include promotion of cell proliferation, tumor growth, angiogenesis, cancer metastasis, drug resistance, and modulation of immune activation (Chiou et al., 2018; Dixson et al., 2023; Li et al., 2021; Patton et al., 2015). EV‐mediated delivery of therapeutic RNAs such as siRNAs or mRNAs is being actively explored for treatment of human disease (Cecchin et al., 2023; Murphy et al., 2019).…”

Section: Introductionmentioning

confidence: 99%

Culture conditions greatly impact the levels of vesicular and extravesicular Ago2 and RNA in extracellular vesicle preparations

Jimenez,

Barman,

Jung

et al. 2023

J of Extracellular Vesicle

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Extracellular vesicle (EV)‐carried miRNAs can influence gene expression and functional phenotypes in recipient cells. Argonaute 2 (Ago2) is a key miRNA‐binding protein that has been identified in EVs and could influence RNA silencing. However, Ago2 is in a non‐vesicular form in serum and can be an EV contaminant. In addition, RNA‐binding proteins (RBPs), including Ago2, and RNAs are often minor EV components whose sorting into EVs may be regulated by cell signaling state. To determine the conditions that influence detection of RBPs and RNAs in EVs, we evaluated the effect of growth factors, oncogene signaling, serum, and cell density on the vesicular and nonvesicular content of Ago2, other RBPs, and RNA in small EV (SEV) preparations. Media components affected both the intravesicular and extravesicular levels of RBPs and miRNAs in EVs, with serum contributing strongly to extravesicular miRNA contamination. Furthermore, isolation of EVs from hollow fiber bioreactors revealed complex preparations, with multiple EV‐containing peaks and a large amount of extravesicular Ago2/RBPs. Finally, KRAS mutation impacts the detection of intra‐ and extra‐vesicular Ago2. These data indicate that multiple cell culture conditions and cell states impact the presence of RBPs in EV preparations, some of which can be attributed to serum contamination.

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Extracellular vesicles: The next generation in gene therapy delivery

Cited by 60 publications

References 53 publications

Differences and Similarities of the Intravenously Administered Lipid Nanoparticles in Three Clinical Trials: Potential Linkage between Lipid Nanoparticles and Extracellular Vesicles

Differences and Similarities of the Intravenously Administered Lipid Nanoparticles in Three Clinical Trials: Potential Linkage between Lipid Nanoparticles and Extracellular Vesicles

Rapid and high yield isolation of extracellular vesicles with purity by application of size exclusion fast performance liquid chromatography

Culture conditions greatly impact the levels of vesicular and extravesicular Ago2 and RNA in extracellular vesicle preparations

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