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

Byrnes, Amy E., Dominguez, 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, Juan, Lin, Jessica, Hinz, Flora I., Friedman, Brad A., Easton, Amy, Hoogenraad, Casper C.·2023·Molecular Therapy - Nucleic Acids
DOI 10.1016/j.omtn.2023.05.005PMC PMC10280097
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Graphical abstract CC BY-NC-ND · PubMed Central
Figure 1 ASOs taken up via gymnosis are active in neurons, microglia, and astrocytes following i.c.v. injection (A) C57BL/6N mice were i.c.v. injected with saline or 100 μg TA1, and analyzed over 14 days. Illustration created using BioRender.com. (B) Acute toxicity 1 h post injection. (C) Percent body weight change normalized to day 0, showing no acute toxicity over the course of the experiment. Error bars cannot be visualized as plotted. (D and E) Representative IF images of brain sections stained for TA1. (D) Coronal brain section stained 2 days post injection of 100 μg TA1. Scale bars, 2 mm and 500 μm (inset). (E) TA1 colocalizes with NeuN (left) as well as Iba1 (right) 14 days post injection of 100 μg TA1. Scale bars, 100 μm. (F–J) Neurons, microglia, and astrocytes were FACS sorted and analyzed for TMEM106b mRNA expression levels 14 days post saline (n = 4) or TA1 (100 μg, n = 4) i.c.v. injection. (F) Gating strategy for cell-specific FACS sorting. (G–J) Relative TMEM106b mRNA expression levels in unsorted brain (G), and sorted neurons (H), microglia (I), or astrocytes (J) as assessed by qRT-PCR. Data were normalized to actin- and saline-treated samples. For all panels, mean ± SEM are shown. Unpaired two-tailed Student’s t test, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001.
Figure 1 ASOs taken up via gymnosis are active in neurons, microglia, and astrocytes following i.c.v. injection (A) C57BL/6N mice were i.c.v. injected with saline or 100 μg TA1, and analyzed over 14 days. Illustration created using BioRender.com. (B) Acute toxicity 1 h post injection. (C) Percent body weight change normalized to day 0, showing no acute toxicity over the course of the experiment. Error bars cannot be visualized as plotted. (D and E) Representative IF images of brain sections stained for TA1. (D) Coronal brain section stained 2 days post injection of 100 μg TA1. Scale bars, 2 mm and 500 μm (inset). (E) TA1 colocalizes with NeuN (left) as well as Iba1 (right) 14 days post injection of 100 μg TA1. Scale bars, 100 μm. (F–J) Neurons, microglia, and astrocytes were FACS sorted and analyzed for TMEM106b mRNA expression levels 14 days post saline (n = 4) or TA1 (100 μg, n = 4) i.c.v. injection. (F) Gating strategy for cell-specific FACS sorting. (G–J) Relative TMEM106b mRNA expression levels in unsorted brain (G), and sorted neurons (H), microglia (I), or astrocytes (J) as assessed by qRT-PCR. Data were normalized to actin- and saline-treated samples. For all panels, mean ± SEM are shown. Unpaired two-tailed Student’s t test, ∗∗p < 0.01, ∗∗∗p < 0.001, ∗∗∗∗p < 0.0001.CC BY-NC-ND · PubMed Central
Figure 2 LNP delivery increases ASO potency in murine primary CNS cell cultures (A–C) TMEM106b mRNA expression in cortical neurons (teal), microglia (burgundy), astrocytes (blue), and OPCs (salmon) as assessed by qRT-PCR. (A) Cells were treated with 10 μM NC1 or TA2, and TMEM106b mRNA expression was analyzed after 3 days. (B) Dose-response curves analyzing TMEM106b mRNA expression after 3 days of TA2 treatment. (C) TMEM106b mRNA expression after 0, 4, 8, 16, 24, 48, 72, 144, and 192 h of treatment with 500 nM TA2. (D) Representative z-projection IF images of cells treated with 5 μM TA2 for 3 days (EC90-95). Scale bars, 25 μm. (E–H) TA2 dose-response curves generated in neurons treated for 3 days with 20 μM bicuculline (E), 1 μM TTX (F), 5 mM KCl (G), or 5 μM glutamate (H) and compared with non-treated (NT) cultures (teal). (I and J) TA2 dose-response curves generated in microglia treated for 3 days with 1× LPS (I) or 20 ng/mL IL-4+IL-13 (J) and compared with NT cultures (burgundy). (K) Cells were treated with 2, 4, 20, 100, and 500 nM TA2-LNPs (dashed) and compared with gymnosis controls (solid), showing increased potency with LNP delivery. TMEM106b mRNA expression was analyzed by qRT-PCR after 3 days. (L) Representative z-projection IF images of cells treated with 100 nM TA2-LNPs for 3 days (EC90-95). Scale bars, 25 μm. Gymnosis dose-response curves were generated using 2, 4, 20, 100, 500, 2,500, 5,000, and 10,000 nM TA2. All mRNA expression data were normalized to GAPDH- and PBS-treated control cells. Three internal replicates were averaged and experiments were completed in triplicate, mean ± SEM are shown.
Figure 2 LNP delivery increases ASO potency in murine primary CNS cell cultures (A–C) TMEM106b mRNA expression in cortical neurons (teal), microglia (burgundy), astrocytes (blue), and OPCs (salmon) as assessed by qRT-PCR. (A) Cells were treated with 10 μM NC1 or TA2, and TMEM106b mRNA expression was analyzed after 3 days. (B) Dose-response curves analyzing TMEM106b mRNA expression after 3 days of TA2 treatment. (C) TMEM106b mRNA expression after 0, 4, 8, 16, 24, 48, 72, 144, and 192 h of treatment with 500 nM TA2. (D) Representative z-projection IF images of cells treated with 5 μM TA2 for 3 days (EC90-95). Scale bars, 25 μm. (E–H) TA2 dose-response curves generated in neurons treated for 3 days with 20 μM bicuculline (E), 1 μM TTX (F), 5 mM KCl (G), or 5 μM glutamate (H) and compared with non-treated (NT) cultures (teal). (I and J) TA2 dose-response curves generated in microglia treated for 3 days with 1× LPS (I) or 20 ng/mL IL-4+IL-13 (J) and compared with NT cultures (burgundy). (K) Cells were treated with 2, 4, 20, 100, and 500 nM TA2-LNPs (dashed) and compared with gymnosis controls (solid), showing increased potency with LNP delivery. TMEM106b mRNA expression was analyzed by qRT-PCR after 3 days. (L) Representative z-projection IF images of cells treated with 100 nM TA2-LNPs for 3 days (EC90-95). Scale bars, 25 μm. Gymnosis dose-response curves were generated using 2, 4, 20, 100, 500, 2,500, 5,000, and 10,000 nM TA2. All mRNA expression data were normalized to GAPDH- and PBS-treated control cells. Three internal replicates were averaged and experiments were completed in triplicate, mean ± SEM are shown.CC BY-NC-ND · PubMed Central
Figure 3 LNP uptake differentially affects ASO delivery and trafficking in primary CNS cells (A) Representative z-projection IF images of cortical neurons, microglia, astrocytes, and OPCs treated for 3 days with 5 μM TA2 or 100 nM TA2-LNPs (EC90-95) showing ASO localization (green) with endolysosomal markers EEA1, LAMP1, and GRASP1 (red). Scale bars, 10 μm and 5 μm (inset). (B–E) Mean Mander’s coefficients quantifying the fraction of overlap/colocalization between TA2 and EEA1, LAMP1, or GRASP1 after 3 days of gymnosis (solid) or LNP delivery (checked) in cortical neurons (B), microglia (C), astrocytes (D), or OPCs (E). ASO signal within and on the membrane was analyzed from single-plane manually thresholded images. Unpaired two-tailed Mann-Whitney test, ∗∗∗∗p < 0.0001. (F) Representative 2D deconvolved IF images showing ASO colocalization with LAMP1 in cortical neurons (left) and microglia (right) after 3 days of gymnosis or LNP delivery. Scale bars, 2 μm. (G) Internalized TA2 concentrations in cortical neurons and microglia after gymnosis or ASO-LNP delivery as determined by MOL-PCR. Cells were treated with 100 nM final ASO concentration for 24 h, mean ± SEM are shown (n = 3). Unpaired two-tailed Student’s t test, ∗∗∗p < 0.001.
Figure 3 LNP uptake differentially affects ASO delivery and trafficking in primary CNS cells (A) Representative z-projection IF images of cortical neurons, microglia, astrocytes, and OPCs treated for 3 days with 5 μM TA2 or 100 nM TA2-LNPs (EC90-95) showing ASO localization (green) with endolysosomal markers EEA1, LAMP1, and GRASP1 (red). Scale bars, 10 μm and 5 μm (inset). (B–E) Mean Mander’s coefficients quantifying the fraction of overlap/colocalization between TA2 and EEA1, LAMP1, or GRASP1 after 3 days of gymnosis (solid) or LNP delivery (checked) in cortical neurons (B), microglia (C), astrocytes (D), or OPCs (E). ASO signal within and on the membrane was analyzed from single-plane manually thresholded images. Unpaired two-tailed Mann-Whitney test, ∗∗∗∗p < 0.0001. (F) Representative 2D deconvolved IF images showing ASO colocalization with LAMP1 in cortical neurons (left) and microglia (right) after 3 days of gymnosis or LNP delivery. Scale bars, 2 μm. (G) Internalized TA2 concentrations in cortical neurons and microglia after gymnosis or ASO-LNP delivery as determined by MOL-PCR. Cells were treated with 100 nM final ASO concentration for 24 h, mean ± SEM are shown (n = 3). Unpaired two-tailed Student’s t test, ∗∗∗p < 0.001.CC BY-NC-ND · PubMed Central
Figure 4 ASO-LNPs induce gliosis in mice following i.c.v. injection (A) TA2-LNP formulations screened for TMEM106b mRNA regulation in vitro. (B and C) TMEM106b mRNA expression in cortical neurons (B) and microglia (C) as determined by qRT-PCR. Cells were treated with 20 nM TA2 (leftmost bar) or TA2-LNP formulations (1–6) for 24 h. Data were normalized to GAPDH- and PBS-treated control cells. Three internal replicates were averaged and the experiments were completed in triplicate. One-way ANOVA with multiple comparisons Dunnett’s test (TA2 control), ∗p < 0.03, ∗∗p < 0.002, ∗∗∗p < 0.0002. (D) Representative cryo-EM images of unloaded, and TA2-loaded GenVoy (formulation 1) and MC3 (formulation 6) LNPs showing the internal structures of the formulations selected for in vivo delivery. Scale bars, 200 nm. (E and F) Particle sizes (E) and polydispersity measurements (F) of unloaded and TA2-loaded LNPs as determined by dynamic light scattering. (G) C57BL/6N mice were i.c.v. injected with saline (n = 6), TA2 (100 or 25 μg, n = 6 per group), TA2-LNPs (25 μg, n = 6 per group), or empty LNPs (n = 3 per group) and analyzed over 14 days. Illustration created using BioRender.com. (H) Acute toxicity 1 h post injection. (I) Percent body weight change normalized to day 0. GenVoy-treated groups showed signs of toxicity and were monitored closely post injection. One mouse in the TA2-GenVoy group did not survive the duration of the experiment. (J) Representative Iba1 IHC images from brain sections obtained 14 days post i.c.v. injection. Scale bars, 500 μm. (K and L) IHC quantification for total (K) and clustered (L) Iba1 signals. For all in vivo statistical analyses, one-way ANOVA with multiple comparisons Dunnett’s test (saline control) was used, ∗p < 0.03, ∗∗p < 0.002, ∗∗∗p < 0.0002, ∗∗∗∗p < 0.0001. Individual group comparisons (empty vs. TA2-loaded LNPs) were analyzed using unpaired two-tailed Student’s t test, ∗p < 0.05. For all panels, mean ± SEM are shown and the 100 μg TA2 dose is represented by bold font.
Figure 4 ASO-LNPs induce gliosis in mice following i.c.v. injection (A) TA2-LNP formulations screened for TMEM106b mRNA regulation in vitro. (B and C) TMEM106b mRNA expression in cortical neurons (B) and microglia (C) as determined by qRT-PCR. Cells were treated with 20 nM TA2 (leftmost bar) or TA2-LNP formulations (1–6) for 24 h. Data were normalized to GAPDH- and PBS-treated control cells. Three internal replicates were averaged and the experiments were completed in triplicate. One-way ANOVA with multiple comparisons Dunnett’s test (TA2 control), ∗p < 0.03, ∗∗p < 0.002, ∗∗∗p < 0.0002. (D) Representative cryo-EM images of unloaded, and TA2-loaded GenVoy (formulation 1) and MC3 (formulation 6) LNPs showing the internal structures of the formulations selected for in vivo delivery. Scale bars, 200 nm. (E and F) Particle sizes (E) and polydispersity measurements (F) of unloaded and TA2-loaded LNPs as determined by dynamic light scattering. (G) C57BL/6N mice were i.c.v. injected with saline (n = 6), TA2 (100 or 25 μg, n = 6 per group), TA2-LNPs (25 μg, n = 6 per group), or empty LNPs (n = 3 per group) and analyzed over 14 days. Illustration created using BioRender.com. (H) Acute toxicity 1 h post injection. (I) Percent body weight change normalized to day 0. GenVoy-treated groups showed signs of toxicity and were monitored closely post injection. One mouse in the TA2-GenVoy group did not survive the duration of the experiment. (J) Representative Iba1 IHC images from brain sections obtained 14 days post i.c.v. injection. Scale bars, 500 μm. (K and L) IHC quantification for total (K) and clustered (L) Iba1 signals. For all in vivo statistical analyses, one-way ANOVA with multiple comparisons Dunnett’s test (saline control) was used, ∗p < 0.03, ∗∗p < 0.002, ∗∗∗p < 0.0002, ∗∗∗∗p < 0.0001. Individual group comparisons (empty vs. TA2-loaded LNPs) were analyzed using unpaired two-tailed Student’s t test, ∗p < 0.05. For all panels, mean ± SEM are shown and the 100 μg TA2 dose is represented by bold font.CC BY-NC-ND · PubMed Central
Figure 5 Transcriptomic analysis characterizing ASO-LNP-mediated gliosis (A–D) Volcano plots of differential gene expression profiles from pairwise comparisons of TA2 (100 μg) vs. saline (A), TA2 (25 μg) vs. saline (B), TA2-GenVoy(1) vs. GenVoy(1) (C), and TA2-MC3(6) vs. MC3(6) (D). Red dots represent FDR < 0.05 and absolute log fold change (logFC) > 1, blue dots represent FDR < 0.05 and absolute logFC < 1, green dots represent FDR > 0.05 and absolute logFC > 1, and gray dots represent FDR > 0.05 and absolute logFC < 1. (E) UpSet plot of direction stratified overlaps between significant (FDR < 0.05 and absolute logFC > 1) differentially expressed genes (DEGs) from all pairwise comparisons. (F) Heatmap of hierarchical clustering analysis of significant (FDR < 0.05 and absolute logFC > 1) DEGs from all pairwise comparisons. (G–K) Gene set scores and select genes for microglia (G), interferon (H), OAS antiviral response (I), trafficking and processing of endosomal TLR (J), and lysosome (K). (L) TMEM106b mRNA expression levels. Gene set score comparisons were analyzed using unpaired two-tailed Student’s t test, ∗p < 0.05. Individual gene comparisons were calculated using voom-limma, ∗FDR < 0.05.
Figure 5 Transcriptomic analysis characterizing ASO-LNP-mediated gliosis (A–D) Volcano plots of differential gene expression profiles from pairwise comparisons of TA2 (100 μg) vs. saline (A), TA2 (25 μg) vs. saline (B), TA2-GenVoy(1) vs. GenVoy(1) (C), and TA2-MC3(6) vs. MC3(6) (D). Red dots represent FDR < 0.05 and absolute log fold change (logFC) > 1, blue dots represent FDR < 0.05 and absolute logFC < 1, green dots represent FDR > 0.05 and absolute logFC > 1, and gray dots represent FDR > 0.05 and absolute logFC < 1. (E) UpSet plot of direction stratified overlaps between significant (FDR < 0.05 and absolute logFC > 1) differentially expressed genes (DEGs) from all pairwise comparisons. (F) Heatmap of hierarchical clustering analysis of significant (FDR < 0.05 and absolute logFC > 1) DEGs from all pairwise comparisons. (G–K) Gene set scores and select genes for microglia (G), interferon (H), OAS antiviral response (I), trafficking and processing of endosomal TLR (J), and lysosome (K). (L) TMEM106b mRNA expression levels. Gene set score comparisons were analyzed using unpaired two-tailed Student’s t test, ∗p < 0.05. Individual gene comparisons were calculated using voom-limma, ∗FDR < 0.05.CC BY-NC-ND · PubMed Central
Figure 6 ASOs have formulation-dependent brain distribution following i.c.v. injection (A) TMEM106b mRNA expression levels 14 days post i.c.v. injection as assessed by qRT-PCR. Data were normalized to GAPDH- and saline-treated controls. One-way ANOVA with multiple comparisons Dunnett’s test (saline control), ∗∗p < 0.002, ∗∗∗∗p < 0.0001. (B) Internalized TA2 concentration 14 days post i.c.v. injection as determined by MOL-PCR. (C and D) Representative anti-ASO IHC brain sections of free TA2 (100 μg)- or TA2-GenVoy(1) (25 μg)-treated animals 4 days following i.c.v. injection. (C) Hemibrain sections stained for TA2 (red staining). Scale bars, 2,000 μm. (D) TA2 IHC staining showing ASO accumulation in piriform cortical neurons, endothelial cells, and the choroid plexus (red staining). Scale bars, 20 μm. (E) Representative cryo-SEM images showing subcellular TA2 localization, red arrows, in piriform cortical neurons, endothelial cells, and ciliated ependymal cells 4 days after administration. Scale bars, 1 μm. (F) Representative cryo-SEM images showing TA2 localization in macrophages lining the ventricle 4 days following TA2-GenVoy(1) administration, red circles. Scale bars, 2 μm. For all panels, mean ± SEM are shown and the 100 μg TA2 dose is represented by bold font.
Figure 6 ASOs have formulation-dependent brain distribution following i.c.v. injection (A) TMEM106b mRNA expression levels 14 days post i.c.v. injection as assessed by qRT-PCR. Data were normalized to GAPDH- and saline-treated controls. One-way ANOVA with multiple comparisons Dunnett’s test (saline control), ∗∗p < 0.002, ∗∗∗∗p < 0.0001. (B) Internalized TA2 concentration 14 days post i.c.v. injection as determined by MOL-PCR. (C and D) Representative anti-ASO IHC brain sections of free TA2 (100 μg)- or TA2-GenVoy(1) (25 μg)-treated animals 4 days following i.c.v. injection. (C) Hemibrain sections stained for TA2 (red staining). Scale bars, 2,000 μm. (D) TA2 IHC staining showing ASO accumulation in piriform cortical neurons, endothelial cells, and the choroid plexus (red staining). Scale bars, 20 μm. (E) Representative cryo-SEM images showing subcellular TA2 localization, red arrows, in piriform cortical neurons, endothelial cells, and ciliated ependymal cells 4 days after administration. Scale bars, 1 μm. (F) Representative cryo-SEM images showing TA2 localization in macrophages lining the ventricle 4 days following TA2-GenVoy(1) administration, red circles. Scale bars, 2 μm. For all panels, mean ± SEM are shown and the 100 μg TA2 dose is represented by bold font.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Byrnes, A. E., Dominguez, S. L., Yen, C.-W., Laufer, B. I., Foreman, O., Reichelt, M., Lin, H., Sagolla, M., Hötzel, K., Ngu, H., Soendergaard, C., Estevez, A., Lin, H.-C., Goyon, A., Bian, J., Lin, J., Hinz, F. I., Friedman, B. A., Easton, A., & Hoogenraad, C. C.
ORCID
Venue
Molecular Therapy - Nucleic Acids
Publisher
Elsevier BV
Published
2023-06
Volume
32
Pages
773-793
ISSN
2162-2531
DOI
10.1016/j.omtn.2023.05.005
PMC
PMC10280097
Cited by
38
References
22
Language
en
Licence
Funders
  • Genentech Inc
  • Roche

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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