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Systemic enzyme delivery by blood-brain barrier-penetrating SapC-DOPS nanovesicles for treatment of neuronopathic Gaucher disease

Sun, Ying, Liou, Benjamin, Chu, Zhengtao, Fannin, Venette, Blackwood, Rachel, Peng, Yanyan, Grabowski, Gregory A., Davis, Harold W., Qi, Xiaoyang·2020·eBioMedicine
DOI 10.1016/j.ebiom.2020.102735PMC PMC7251241
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Fig. 1 SapC-DOPS activates GCase. (a) SapC-DOPS and SapC similarly activate GCase in a cell- free assay. DOPS is a control. SapC, 0 to 500 nM; DOPS, 0 - 4500 nM. Free GCase incubated with SapC-DOPS or SapC for 30 min before determining the GCase activity. (b) SapC-DOPS increases GCase activity in fibroblasts from SapC-deficient mice (4 L;C* and SapC-/-). The cultured cells were incubated with 100 nM SapC-DOPS for 30 min before harvesting for GCase activity assay. Student's t-test. ***, p<0.0001. (c) Kd of GCase interaction with SapC-DOPS compared to SapB-DOPS. (d) Kd of SapC interaction with DOPS compared to SapB with DOPS. The Kd values were determined by microscale thermophoresis (MST) using Affinity Analysis v2.1.3 software. (e) Functional domain of SapC. GCase activity in 4 L;C* fibroblasts treated with WT SapC, mutant SapCs or WT SapB formulated with DOPS-GCase. The cells were incubated for 5 days with two changes of fresh medium with the formulation. One-Way ANOVA with Tukey's multiple comparison test. ***, p <0.05. The samples were assayed in triplicates/experiment of 2–3 independent experiments.
Fig. 1 SapC-DOPS activates GCase. (a) SapC-DOPS and SapC similarly activate GCase in a cell- free assay. DOPS is a control. SapC, 0 to 500 nM; DOPS, 0 - 4500 nM. Free GCase incubated with SapC-DOPS or SapC for 30 min before determining the GCase activity. (b) SapC-DOPS increases GCase activity in fibroblasts from SapC-deficient mice (4 L;C* and SapC-/-). The cultured cells were incubated with 100 nM SapC-DOPS for 30 min before harvesting for GCase activity assay. Student's t-test. ***, p<0.0001. (c) Kd of GCase interaction with SapC-DOPS compared to SapB-DOPS. (d) Kd of SapC interaction with DOPS compared to SapB with DOPS. The Kd values were determined by microscale thermophoresis (MST) using Affinity Analysis v2.1.3 software. (e) Functional domain of SapC. GCase activity in 4 L;C* fibroblasts treated with WT SapC, mutant SapCs or WT SapB formulated with DOPS-GCase. The cells were incubated for 5 days with two changes of fresh medium with the formulation. One-Way ANOVA with Tukey's multiple comparison test. ***, p <0.05. The samples were assayed in triplicates/experiment of 2–3 independent experiments.CC BY-NC-ND · PubMed Central
Fig. 2 SapC-DOPS nanovesicles preserve GCase. Cellular GCase activity (a) and GCase protein (b) of mouse Gba1-/- fibroblasts that were incubated for 24 or 48 h with SapC-DOPS-GCase and GCase, respectively. SapC-DOPS-GCase incubated cells showed higher levels of GCase activity and protein than GCase incubated cells. (c) GCase activity of human GD2 and GD3 fibroblasts, GM1260 (L444P/P415R) and GM877 (L444P/L444P), incubated with SapC-DOPS-GCase for 24 h. (d) Human GCase (green) detected in the lysosome (Lamp2a, red) of Gba1-/- fibroblasts incubated with SapC-DOPS- GCase and GCase for 24 h. The cells with SapC-DOPS-GCase showed higher PCC (Person correlation coefficient) compared to GCase incubated cells (n = 8–14 cells), indicating more GCase targeting to lysosomes in SapC-DOPS-GCase incubated cells compared to free GCase incubated cells. Scale bar =100 µm for all images. (e) Effect of mannan on GCase uptake. J774E macrophages and Gba1-/- neurons were incubated with 80 µg GCase/mL of SapC-DOPS-GCase or free GCase in the presence and absence of mannan (2 mg/mL). All the cells used for the assays were washed prior to collection. The data presents net GCase activity (increased GCase activity level minus basal/endogenous GCase activity level). The samples were assayed in triplicates/experiment of 2–3 independent experiments.
Fig. 2 SapC-DOPS nanovesicles preserve GCase. Cellular GCase activity (a) and GCase protein (b) of mouse Gba1-/- fibroblasts that were incubated for 24 or 48 h with SapC-DOPS-GCase and GCase, respectively. SapC-DOPS-GCase incubated cells showed higher levels of GCase activity and protein than GCase incubated cells. (c) GCase activity of human GD2 and GD3 fibroblasts, GM1260 (L444P/P415R) and GM877 (L444P/L444P), incubated with SapC-DOPS-GCase for 24 h. (d) Human GCase (green) detected in the lysosome (Lamp2a, red) of Gba1-/- fibroblasts incubated with SapC-DOPS- GCase and GCase for 24 h. The cells with SapC-DOPS-GCase showed higher PCC (Person correlation coefficient) compared to GCase incubated cells (n = 8–14 cells), indicating more GCase targeting to lysosomes in SapC-DOPS-GCase incubated cells compared to free GCase incubated cells. Scale bar =100 µm for all images. (e) Effect of mannan on GCase uptake. J774E macrophages and Gba1-/- neurons were incubated with 80 µg GCase/mL of SapC-DOPS-GCase or free GCase in the presence and absence of mannan (2 mg/mL). All the cells used for the assays were washed prior to collection. The data presents net GCase activity (increased GCase activity level minus basal/endogenous GCase activity level). The samples were assayed in triplicates/experiment of 2–3 independent experiments.CC BY-NC-ND · PubMed Central
Fig. 3 Tissue distribution of SapC-DOPS-GCase. (a to e) 4 L;C* and WT mice at 38 days of age were i.v. infused with one bolus injection of SapC-DOPS-GCase, vehicle (CP buffer) or free GCase (54.6 mg/kg SapC-DOPS and 0.4 mg/kg GCase; 0.4 mg/kg free GCase). Tissues were collected 3 h post injection or as indicated. (a to c) GCase protein detected by immunoprecipitation followed with immunoblot in 4 L;C* (a) and WT (b) brains with SapC-DOPS-GCase. (c) GCase protein detected in the 4 L;C* brains and livers at 1 to 24 h post injection with SapC-DOPS-GCase. (d) GCase activity increased in SapC-DOPS-GCase treated brains. (e) GCase protein detected in the 4 L;C* liver. Human GCase (20 ng) is a loading control in A and E. (f) GCase activity in 4 L;C* mouse tissues at 49 days of age treated with SapC-DOPS-GCase, free GCase or vehicle-CP buffer (2 h post i.p. injection of, 2 x injection/2 h). SapC-DOPS-GCase was distributed to liver, spleen, lung, lymph nodes and bone marrow cells. SapC-DOPS-GCase-treated mice have significantly higher activity in those tissues than free GCase-treated mice. (g-k) Distribution of human GCase in brain regions of 4 L;C* mice at 38 days of age treated with SapC-DOPS-GCase or free GCase (3 h post one bolus i.v. injection). (g) Human GCase (green) co-stained with VCAM 1 (red) positive endothelium by immunofluorescence (IF) in SapC-DOPS-GCase treated 4 L;C* mouse brain. Scale bar is 20 μm. (h) Human GCase (green) detected by IF in the lysosome (Lamp2a, red) of brain cells. No GCase is detected in free GCase treated 4 L;C* brains. Image magnifications are 400x. (i) Panel: representative images of GCase protein (green) detected by IF in astrocytes (red, GFAP), neurons (red, NeuN) and microglia (red, CD68) in SapC- DOPS-GCase-treated 4 L;C* mouse brains. Scale bar = 10 µm for all images. (j) The graph shows the percentage of brain cells containing GCase. (k) Human GCase positive cells (green stars) determined by IF were distributed in 4 L;C* mouse brain regions that show inflammation stained with anti-CD68 (brown). Hematoxylin stains nuclei (blue). Scale bar is 3 mm. n = 3 mice, replicated assays of 2- 3 independent experiments, n = > 5 images/mouse. Student's t-test. *, p < 0.05; **, p < 0.01; ***, p < 0.001.
Fig. 3 Tissue distribution of SapC-DOPS-GCase. (a to e) 4 L;C* and WT mice at 38 days of age were i.v. infused with one bolus injection of SapC-DOPS-GCase, vehicle (CP buffer) or free GCase (54.6 mg/kg SapC-DOPS and 0.4 mg/kg GCase; 0.4 mg/kg free GCase). Tissues were collected 3 h post injection or as indicated. (a to c) GCase protein detected by immunoprecipitation followed with immunoblot in 4 L;C* (a) and WT (b) brains with SapC-DOPS-GCase. (c) GCase protein detected in the 4 L;C* brains and livers at 1 to 24 h post injection with SapC-DOPS-GCase. (d) GCase activity increased in SapC-DOPS-GCase treated brains. (e) GCase protein detected in the 4 L;C* liver. Human GCase (20 ng) is a loading control in A and E. (f) GCase activity in 4 L;C* mouse tissues at 49 days of age treated with SapC-DOPS-GCase, free GCase or vehicle-CP buffer (2 h post i.p. injection of, 2 x injection/2 h). SapC-DOPS-GCase was distributed to liver, spleen, lung, lymph nodes and bone marrow cells. SapC-DOPS-GCase-treated mice have significantly higher activity in those tissues than free GCase-treated mice. (g-k) Distribution of human GCase in brain regions of 4 L;C* mice at 38 days of age treated with SapC-DOPS-GCase or free GCase (3 h post one bolus i.v. injection). (g) Human GCase (green) co-stained with VCAM 1 (red) positive endothelium by immunofluorescence (IF) in SapC-DOPS-GCase treated 4 L;C* mouse brain. Scale bar is 20 μm. (h) Human GCase (green) detected by IF in the lysosome (Lamp2a, red) of brain cells. No GCase is detected in free GCase treated 4 L;C* brains. Image magnifications are 400x. (i) Panel: representative images of GCase protein (green) detected by IF in astrocytes (red, GFAP), neurons (red, NeuN) and microglia (red, CD68) in SapC- DOPS-GCase-treated 4 L;C* mouse brains. Scale bar = 10 µm for all images. (j) The graph shows the percentage of brain cells containing GCase. (k) Human GCase positive cells (green stars) determined by IF were distributed in 4 L;C* mouse brain regions that show inflammation stained with anti-CD68 (brown). Hematoxylin stains nuclei (blue). Scale bar is 3 mm. n = 3 mice, replicated assays of 2- 3 independent experiments, n = > 5 images/mouse. Student's t-test. *, p < 0.05; **, p < 0.01; ***, p < 0.001.CC BY-NC-ND · PubMed Central
Fig. 4 Therapeutic efficacy of Sap-DOPS-GCase. 4 L;C* mice were treated with SapC-DOPS-GCase and vehicle or free GCase by daily i.p. injections of SapC-DOPS-GCase from day 21 to 27 followed by tail i.v. vein injection from day 28 to terminal age, 3 times per week . (a) Hindlimb clasping was significantly improved in SapC-DOPS-GCase treated 4 L;C* mice compared to saline treated 4 L;C* mice. 4 L;WT mice is the normal control. ANOVA test. **, p < 0.01; ***, p < 0.001. (b) Sap-DOPS-GCase treatment significantly improved right and left strides of 4 L;C* mice at 50 and 55 days of age compared to vehicle (CP buffer) or saline control. Student's t-test. ***, p < 0.001. (c) Compared to free GCase, vehicle and untreated 4 L;C* mice, SapC-DOPS-GCase treatment significantly prolonged survival of 4 L;C* mice. Log-Rank (Mantel-Cox) test (p<0.05). (d) GCase substrate, GluCer was significantly reduced in treated 4 L;C* brain (n = 3, 50 days of age). Student's t-test (p<0.05). (e) Treated 4 L;C* brain regions (cortex, thalamus, brain stem and midbrain) showed significantly reduced inflammation determined by anti-GFAP (astrocyte) staining (n = 3, 50 days of age). The signal densities of GFAP, were quantified with Image J software and presented as a bar graph. Scale bar is the same for all images. n = >5 images /mouse. Student's t-test. ***, p < 0.001.
Fig. 4 Therapeutic efficacy of Sap-DOPS-GCase. 4 L;C* mice were treated with SapC-DOPS-GCase and vehicle or free GCase by daily i.p. injections of SapC-DOPS-GCase from day 21 to 27 followed by tail i.v. vein injection from day 28 to terminal age, 3 times per week . (a) Hindlimb clasping was significantly improved in SapC-DOPS-GCase treated 4 L;C* mice compared to saline treated 4 L;C* mice. 4 L;WT mice is the normal control. ANOVA test. **, p < 0.01; ***, p < 0.001. (b) Sap-DOPS-GCase treatment significantly improved right and left strides of 4 L;C* mice at 50 and 55 days of age compared to vehicle (CP buffer) or saline control. Student's t-test. ***, p < 0.001. (c) Compared to free GCase, vehicle and untreated 4 L;C* mice, SapC-DOPS-GCase treatment significantly prolonged survival of 4 L;C* mice. Log-Rank (Mantel-Cox) test (p<0.05). (d) GCase substrate, GluCer was significantly reduced in treated 4 L;C* brain (n = 3, 50 days of age). Student's t-test (p<0.05). (e) Treated 4 L;C* brain regions (cortex, thalamus, brain stem and midbrain) showed significantly reduced inflammation determined by anti-GFAP (astrocyte) staining (n = 3, 50 days of age). The signal densities of GFAP, were quantified with Image J software and presented as a bar graph. Scale bar is the same for all images. n = >5 images /mouse. Student's t-test. ***, p < 0.001.CC BY-NC-ND · PubMed Central
Fig. 5 SapC-DOPS in vitro and in vivo efficacy. (a) SapC-DOPS-CVM (red) detected in the thalamus region of 4 L;C* mouse brain that has inflammation stained positive by anti-CD68 (brown). SapC-DOPS-CVM also showed in control 4 L;WT mice brain that has no inflammation. Magnification of images are 100x. Bar graph showed CVM levels in 4 L;C* and control mice brain in thalamus region. 4 L;C* mice at 40 days of age were i.v. injected with 200 µL SapC-DOPS-CVM (SapC = 0.4 mg/mL, DOPS = 0.082 mg/mL, CVM = 0.04 µM). Tissues were collected 24 h post injection. (b-d) 4 L;C* mice were administered with SapC-DOPS, SapC-DOPS-GCase or vehicle (CP buffer) by daily i.p. injections of SapC-DOPS or SapC-DOPS-GCase from day 21 to 27, followed by tail i.v. vein injection of SapC-DOPS or SapC-DOPS-GCase, 3 times per week, from day 28 to terminal age. (b) Increased GCase activity in the brain of 4 L;C* mice treated with SapC-DOPS (n = 3, 40 days of age). Student's t-test. **, p < 0.01. (c) SapC-DOPS treated 4 L;C* mice showed significantly prolonged survival compared to vehicel-4 L;C*. The survival is longer in SapC-DOPS-GCase-treated 4 L;C* compared to SapC-DOPS-treated 4 L;C* mice. Log-Rank (Mantel-Cox) test (p<0.05). (d) In comparison to SapC-DOPS, SapC-DOPS-GCase treated 4 L;C* mice showed significant improved left stride and right stride at 45 days of age (n = 6). Student's t-test. *, p < 0.05.
Fig. 5 SapC-DOPS in vitro and in vivo efficacy. (a) SapC-DOPS-CVM (red) detected in the thalamus region of 4 L;C* mouse brain that has inflammation stained positive by anti-CD68 (brown). SapC-DOPS-CVM also showed in control 4 L;WT mice brain that has no inflammation. Magnification of images are 100x. Bar graph showed CVM levels in 4 L;C* and control mice brain in thalamus region. 4 L;C* mice at 40 days of age were i.v. injected with 200 µL SapC-DOPS-CVM (SapC = 0.4 mg/mL, DOPS = 0.082 mg/mL, CVM = 0.04 µM). Tissues were collected 24 h post injection. (b-d) 4 L;C* mice were administered with SapC-DOPS, SapC-DOPS-GCase or vehicle (CP buffer) by daily i.p. injections of SapC-DOPS or SapC-DOPS-GCase from day 21 to 27, followed by tail i.v. vein injection of SapC-DOPS or SapC-DOPS-GCase, 3 times per week, from day 28 to terminal age. (b) Increased GCase activity in the brain of 4 L;C* mice treated with SapC-DOPS (n = 3, 40 days of age). Student's t-test. **, p < 0.01. (c) SapC-DOPS treated 4 L;C* mice showed significantly prolonged survival compared to vehicel-4 L;C*. The survival is longer in SapC-DOPS-GCase-treated 4 L;C* compared to SapC-DOPS-treated 4 L;C* mice. Log-Rank (Mantel-Cox) test (p<0.05). (d) In comparison to SapC-DOPS, SapC-DOPS-GCase treated 4 L;C* mice showed significant improved left stride and right stride at 45 days of age (n = 6). Student's t-test. *, p < 0.05.CC BY-NC-ND · PubMed Central
Fig. 6 Phosphatidylserine (PS)-mediated inflamed brain targeting determined by PS-binding protein, lactadherin (Lact). (a and b) Lact blocked SapC-DOPS-CVM targeting into 4 L;C* mouse brains. (a) Significantly diminished CVM signals were observed in 4 L;C* brains i.v. injected with Lact compared with BSA of whole brain and saggital brain cuts. Non-symptomatic, non-injected littermate, 4 L/WT, brains, used as controls, have no CVM signal. (b) Relative CVM signal levels are shown in the graph. CVM signals were acquired by ex-vivo IVIS imaging. Student's t-test (n = 4 mice). (c and d) Lact distributes in neural cells and inflamed brain regions. 4 L;C* and 4 L/WT control mice were injected with 100 or 200 µL of Lact (83 µg/mL) by i.v. The brain sections were stained with anti-lactadherin-FITC (green) in combination with anti-CD68 (microglia, red), anti-Tuj1 (Neuron, red) and anti-VCAM1 (endothelium, red). (c) Lact signals were around microglia and neuron cells, and on endothelium. (d) Signal levels (RFU, relative fluorescence unit) of Lact in inflamed 4 L;C* brain regions. Student's t-test (n = 4 mice). *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001.
Fig. 6 Phosphatidylserine (PS)-mediated inflamed brain targeting determined by PS-binding protein, lactadherin (Lact). (a and b) Lact blocked SapC-DOPS-CVM targeting into 4 L;C* mouse brains. (a) Significantly diminished CVM signals were observed in 4 L;C* brains i.v. injected with Lact compared with BSA of whole brain and saggital brain cuts. Non-symptomatic, non-injected littermate, 4 L/WT, brains, used as controls, have no CVM signal. (b) Relative CVM signal levels are shown in the graph. CVM signals were acquired by ex-vivo IVIS imaging. Student's t-test (n = 4 mice). (c and d) Lact distributes in neural cells and inflamed brain regions. 4 L;C* and 4 L/WT control mice were injected with 100 or 200 µL of Lact (83 µg/mL) by i.v. The brain sections were stained with anti-lactadherin-FITC (green) in combination with anti-CD68 (microglia, red), anti-Tuj1 (Neuron, red) and anti-VCAM1 (endothelium, red). (c) Lact signals were around microglia and neuron cells, and on endothelium. (d) Signal levels (RFU, relative fluorescence unit) of Lact in inflamed 4 L;C* brain regions. Student's t-test (n = 4 mice). *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001.CC BY-NC-ND · PubMed Central

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Cited by

Metadata

Authors
Sun, Y., Liou, B., Chu, Z., Fannin, V., Blackwood, R., Peng, Y., Grabowski, G. A., Davis, H. W., & Qi, X.
ORCID
Sun, Ying
Venue
eBioMedicine
Publisher
Elsevier BV
Published
2020-05
Volume
55
Pages
102735
ISSN
2352-3964
DOI
10.1016/j.ebiom.2020.102735
PMC
PMC7251241
Cited by
39
References
2
Language
en
Licence
Funders
National Institutes of Health (R21NS 095047, R01 NS 086134, UH2 NS092981)

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