Lipid nanoparticle delivery limits antisense oligonucleotide activity and cellular distribution in the brain after intracerebroventricular injection

Byrnes, Amy E.; Domínguez, Sara L.; Yen, Chun-Wan; Laufer, Benjamin I.; Foreman, Oded; Reichelt, Mike; Lin, Han; Sagolla, Meredith; Hötzel, Kathy; Ngu, Hai; Soendergaard, Christoffer; Estevez, Alberto; Lin, Hsiu-Chao; Goyon, Alexandre; Bian, Jinjun; Lin, Jessica; Hinz, Flora I.; Friedman, Brad A.; Easton, Amy; Hoogenraad, Casper C.

doi:10.1016/j.omtn.2023.05.005

Cited by 11 publications

(12 citation statements)

References 77 publications

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“…We utilized microfluidic mixing the encapsulate either ssNC1 or ssASO1 in LNPs containing lipid combinations (formulations 1–4) previously reported to differentially distribute to unique cell types and/or tissues ( Figure 6 A). 16 , 21 , 22 , 23 All particles behaved well post mixing with consistent diameters and polydispersity indices measured using dynamic light scattering. The formulations were then screened for EGFP splice-switching activity in mKate2.ssEGFP.HBB-expressing HEK293 cells ( Figure 6 B).…”

Section: Resultssupporting

confidence: 57%

“…Liver EGFP signal was consistent between 6 and 20 days post dosing, revealing that ASO-LNP-mediated splice-switching is robust over time. However, despite administering a pooled mixture of ASO-LNPs that were previously reported to differentially distribute to the liver or lungs, 16 , 21 , 22 , 23 EGFP signal in the lungs did not change over the course of the experiment. There was also no significant increase in EGFP intensity in the brain, spleen, kidneys, or heart.…”

Section: Resultsmentioning

confidence: 76%

“…Cortical neurons, microglia, and astrocytes were isolated from ki mice using previously reported methods. 16 , 17 All cell types showed robust mKate2 expression as compared to cultures obtained from WT animals ( Figure 3 A). These data are consistent with our in vivo and ex vivo tissue imaging studies ( Figure 2 ), revealing mKate2 fluorescence is a robust marker of transgene expression across unique assays, tissues, and cell types.…”

Section: Resultsmentioning

confidence: 93%

“…These data show that EGFP splice-switching in primary cell cultures is dependent on cell type, ASO concentration, and incubation time and provide a quantitative, high-throughput method of examining ASO activity ubiquitously across cell culture systems.

Figure 3 ASO concentration and incubation time regulate EGFP splice-switching in primary CNS cell cultures (A) Representative images showing mKate2 is robustly expressed in neurons, microglia, and astrocytes cultured 16 , 17 from mKate2.ssEGFP.HBB ki mice. DAPI is shown in white.…”

Section: Resultsmentioning

confidence: 99%

“… (A) Representative images showing mKate2 is robustly expressed in neurons, microglia, and astrocytes cultured 16 , 17 from mKate2.ssEGFP.HBB ki mice. DAPI is shown in white.…”

Section: Resultsmentioning

confidence: 99%

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A fluorescent splice-switching mouse model enables high-throughput, sensitive quantification of antisense oligonucleotide delivery and activity

Byrnes,

Roudnicky,

Gogineni

et al. 2024

Cell Reports Methods

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Section: Resultssupporting

confidence: 57%

Section: Resultsmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

“… (A) Representative images showing mKate2 is robustly expressed in neurons, microglia, and astrocytes cultured 16 , 17 from mKate2.ssEGFP.HBB ki mice. DAPI is shown in white.…”

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

A fluorescent splice-switching mouse model enables high-throughput, sensitive quantification of antisense oligonucleotide delivery and activity

Byrnes,

Roudnicky,

Gogineni

et al. 2024

Cell Reports Methods

Self Cite

View full text Add to dashboard Cite

Physiological Barriers and Strategies of Lipid‐Based Nanoparticles for Nucleic Acid Drug Delivery

Hu,

Li,

You

et al. 2023

Advanced Materials

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Lipid‐based nanoparticles (LBNPs) are currently the most promising vehicles for nucleic acid drug (NAD) delivery. Although their clinical applications have achieved success, the NAD delivery efficiency and safety are still unsatisfactory, which are, to a large extent, due to the existence of multi‐level physiological barriers in vivo. It is important to elucidate the interactions between these barriers and LBNPs, which will guide more rational design of efficient NAD vehicles with low adverse effects and facilitate broader applications of nucleic acid therapeutics. In this review, we describe the obstacles and challenges of biological barriers to NAD delivery at systemic, organ, sub‐organ, cellular and subcellular levels. We comprehensively review the strategies to overcome these barriers, mainly including physically/chemically engineering LBNPs and directly modifying physiological barriers by auxiliary treatments. We then discuss the potentials and challenges for successful translation of these preclinical studies into the clinic. In the end, we address a forward look at the strategies on manipulating protein corona (PC), which may pull off the trick of overcoming those physiological barriers and significantly improve the efficacy and safety of LBNP‐based NADs delivery.This article is protected by copyright. All rights reserved

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Lipid Nanoparticles Optimized for Targeting and Release of Nucleic Acid

Jia,

Wang,

et al. 2023

Advanced Materials

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Lipid nanoparticles (LNPs) are currently the most promising clinical nucleic acids drug delivery vehicles. LNPs prevent the degradation of cargo nucleic acids during blood circulation. Upon entry into the cell, specific components of the lipid nanoparticles can promote the endosomal escape of nucleic acids. These are the basic properties of lipid nanoparticles as nucleic acid carriers. As LNPs exhibit hepatic aggregation characteristics, enhancing targeting out of the liver is a crucial way to improve LNPs administrated in vivo. Meanwhile, endosomal escape of nucleic acids loaded in LNPs is often considered inadequate, and therefore, much effort is devoted to enhancing the intracellular release efficiency of nucleic acids. Here, we concluded different strategies to efficiently deliver nucleic acid delivery from LNPs and investigated their mechanisms. In addition, based on the information on LNPs that are in clinical trials or have completed clinical trials, we discussed the issues that are necessary to be approached in the clinical translation of LNPs, which we hope will shed light on the development of LNP nucleic acid drugs.This article is protected by copyright. All rights reserved

show abstract

Lipid nanoparticle delivery limits antisense oligonucleotide activity and cellular distribution in the brain after intracerebroventricular injection

Cited by 11 publications

References 77 publications

A fluorescent splice-switching mouse model enables high-throughput, sensitive quantification of antisense oligonucleotide delivery and activity

A fluorescent splice-switching mouse model enables high-throughput, sensitive quantification of antisense oligonucleotide delivery and activity

Physiological Barriers and Strategies of Lipid‐Based Nanoparticles for Nucleic Acid Drug Delivery

Lipid Nanoparticles Optimized for Targeting and Release of Nucleic Acid

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