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14 results on '"Ilahibaks, Nazma F."'

4. Extracellular vesicle-mediated delivery of CRISPR/Cas9 ribonucleoprotein complex targeting proprotein convertase subtilisin-kexin type 9 (Pcsk9) in primary mouse hepatocytes

Author

Ilahibaks, Nazma F., Kluiver, Thomas A., de Jong, Olivier G., de Jager, Saskia C.A., Schiffelers, Raymond M., Vader, Pieter, Peng, Weng Chuan, Lei, Zhiyong, Sluijter, Joost P.G., Ilahibaks, Nazma F., Kluiver, Thomas A., de Jong, Olivier G., de Jager, Saskia C.A., Schiffelers, Raymond M., Vader, Pieter, Peng, Weng Chuan, Lei, Zhiyong, and Sluijter, Joost P.G.

Abstract

The loss-of-function of the proprotein convertase subtilisin–kexin type 9 (Pcsk9) gene has been associated with significant reductions in plasma serum low-density lipoprotein cholesterol (LDL-C) levels. Both CRISPR/Cas9 and CRISPR-based editor-mediated Pcsk9 inactivation have successfully lowered plasma LDL-C and PCSK9 levels in preclinical models. Despite the promising preclinical results, these studies did not report how vehicle-mediated CRISPR delivery inactivating Pcsk9 affected low-density lipoprotein receptor recycling in vitro or ex vivo. Extracellular vesicles (EVs) have shown promise as a biocompatible delivery vehicle, and CRISPR/Cas9 ribonucleoprotein (RNP) has been demonstrated to mediate safe genome editing. Therefore, we investigated EV-mediated RNP targeting of the Pcsk9 gene ex vivo in primary mouse hepatocytes. We engineered EVs with the rapamycin-interacting heterodimer FK506-binding protein (FKBP12) to contain its binding partner, the T82L mutant FKBP12-rapamycin binding (FRB) domain, fused to the Cas9 protein. By integrating the vesicular stomatitis virus glycoprotein on the EV membrane, the engineered Cas9 EVs were used for intracellular CRISPR/Cas9 RNP delivery, achieving genome editing with an efficacy of ±28.1% in Cas9 stoplight reporter cells. Administration of Cas9 EVs in mouse hepatocytes successfully inactivated the Pcsk9 gene, leading to a reduction in Pcsk9 mRNA and increased uptake of the low-density lipoprotein receptor and LDL-C. These readouts can be used in future experiments to assess the efficacy of vehicle-mediated delivery of genome editing technologies targeting Pcsk9. The ex vivo data could be a step towards reducing animal testing and serve as a precursor to future in vivo studies for EV-mediated CRISPR/Cas9 RNP delivery targeting Pcsk9.

Published
2024

5. Extracellular vesicles as vehicles for drug delivery to the heart

Author

Experimentele Afd. Cardiologie 2, CDL Nanomedicine, Circulatory Health, Regenerative Medicine and Stem Cells, Onderzoek Cardiovasculair Reg. Med., Ilahibaks, Nazma F, Lei, Zhiyong, Sluijter, Joost P G, Experimentele Afd. Cardiologie 2, CDL Nanomedicine, Circulatory Health, Regenerative Medicine and Stem Cells, Onderzoek Cardiovasculair Reg. Med., Ilahibaks, Nazma F, Lei, Zhiyong, and Sluijter, Joost P G

Published
2024

6. Extracellular vesicle-mediated delivery of CRISPR/Cas9 ribonucleoprotein complex targeting proprotein convertase subtilisin-kexin type 9 (Pcsk9) in primary mouse hepatocytes

Author

Experimentele Afd. Cardiologie 2, CDL Nanomedicine, Circulatory Health, Infection & Immunity, Centraal Diagnostisch Laboratorium, Cancer, CDL Cluster Onderzoek en Onderwijs, Regenerative Medicine and Stem Cells, Onderzoek Cardiovasculair Reg. Med., Ilahibaks, Nazma F, Kluiver, Thomas A, de Jong, Olivier G, de Jager, Saskia C A, Schiffelers, Raymond M, Vader, Pieter, Peng, Weng Chuan, Lei, Zhiyong, Sluijter, Joost P G, Experimentele Afd. Cardiologie 2, CDL Nanomedicine, Circulatory Health, Infection & Immunity, Centraal Diagnostisch Laboratorium, Cancer, CDL Cluster Onderzoek en Onderwijs, Regenerative Medicine and Stem Cells, Onderzoek Cardiovasculair Reg. Med., Ilahibaks, Nazma F, Kluiver, Thomas A, de Jong, Olivier G, de Jager, Saskia C A, Schiffelers, Raymond M, Vader, Pieter, Peng, Weng Chuan, Lei, Zhiyong, and Sluijter, Joost P G

Published
2024

7. Extracellular vesicle-mediated delivery of CRISPR/Cas9 ribonucleoprotein complex targeting proprotein convertase subtilisin-kexin type 9 (Pcsk9) in primary mouse hepatocytes

Author

Afd Pharmaceutics, Sub General Pharmaceutics, Pharmaceutics, Ilahibaks, Nazma F., Kluiver, Thomas A., de Jong, Olivier G., de Jager, Saskia C.A., Schiffelers, Raymond M., Vader, Pieter, Peng, Weng Chuan, Lei, Zhiyong, Sluijter, Joost P.G., Afd Pharmaceutics, Sub General Pharmaceutics, Pharmaceutics, Ilahibaks, Nazma F., Kluiver, Thomas A., de Jong, Olivier G., de Jager, Saskia C.A., Schiffelers, Raymond M., Vader, Pieter, Peng, Weng Chuan, Lei, Zhiyong, and Sluijter, Joost P.G.

Published
2024

9. Extracellular vesicle‐mediated delivery of CRISPR/Cas9 ribonucleoprotein complex targeting proprotein convertase subtilisin‐kexin type 9 (Pcsk9) in primary mouse hepatocytes

Author

Ilahibaks, Nazma F., primary, Kluiver, Thomas A., additional, de Jong, Olivier G., additional, de Jager, Saskia C. A., additional, Schiffelers, Raymond M., additional, Vader, Pieter, additional, Peng, Weng Chuan, additional, Lei, Zhiyong, additional, and Sluijter, Joost P. G., additional

Published
2024
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10. Extracellular vesicle-mediated protein delivery to the liver

Author

Experimentele Afd. Cardiologie 2, Circulatory Health, Infection & Immunity, Centraal Diagnostisch Laboratorium, Cancer, CDL Cluster Onderzoek en Onderwijs, CDL Nanomedicine, Regenerative Medicine and Stem Cells, Onderzoek Cardiovasculair Reg. Med., Ilahibaks, Nazma F, Roefs, Marieke T, Brans, Maike A D, Blok, Christian Snijders, de Jager, Saskia C A, Schiffelers, Raymond M, Vader, Pieter, Lei, Zhiyong, Sluijter, Joost P G, Experimentele Afd. Cardiologie 2, Circulatory Health, Infection & Immunity, Centraal Diagnostisch Laboratorium, Cancer, CDL Cluster Onderzoek en Onderwijs, CDL Nanomedicine, Regenerative Medicine and Stem Cells, Onderzoek Cardiovasculair Reg. Med., Ilahibaks, Nazma F, Roefs, Marieke T, Brans, Maike A D, Blok, Christian Snijders, de Jager, Saskia C A, Schiffelers, Raymond M, Vader, Pieter, Lei, Zhiyong, and Sluijter, Joost P G

Published
2023

11. TOP-EVs: Technology of Protein delivery through Extracellular Vesicles is a versatile platform for intracellular protein delivery

Author

Afd Pharmaceutics, Pharmaceutics, Ilahibaks, Nazma F., Ardisasmita, Arif I., Xie, Songpu, Gunnarsson, Anders, Brealey, Joseph, Vader, Pieter, de Jong, Olivier G., Jager, Saskia de, Dekker, Niek, Peacock, Ben, Schiffelers, Raymond M., Sluijter, Joost P.G., Lei, Zhiyong, Afd Pharmaceutics, Pharmaceutics, Ilahibaks, Nazma F., Ardisasmita, Arif I., Xie, Songpu, Gunnarsson, Anders, Brealey, Joseph, Vader, Pieter, de Jong, Olivier G., Jager, Saskia de, Dekker, Niek, Peacock, Ben, Schiffelers, Raymond M., Sluijter, Joost P.G., and Lei, Zhiyong

Published
2023

12. TOP-EVs: Technology of Protein delivery through Extracellular Vesicles is a versatile platform for intracellular protein delivery

Author

Experimental Cardiology Laboratory, Experimentele Afd. Cardiologie 2, CDL Staf Research, CDL Cluster Onderzoek en Onderwijs, Circulatory Health, CDL Nanomedicine, Centraal Diagnostisch Laboratorium, Cancer, Onderzoek Cardiovasculair Reg. Med., Regenerative Medicine and Stem Cells, Ilahibaks, Nazma F., Ardisasmita, Arif I., Xie, Songpu, Gunnarsson, Anders, Brealey, Joseph, Vader, Pieter, de Jong, Olivier G., de Jager, Saskia, Dekker, Niek, Peacock, Ben, Schiffelers, Raymond M., Sluijter, Joost P.G., Lei, Zhiyong, Experimental Cardiology Laboratory, Experimentele Afd. Cardiologie 2, CDL Staf Research, CDL Cluster Onderzoek en Onderwijs, Circulatory Health, CDL Nanomedicine, Centraal Diagnostisch Laboratorium, Cancer, Onderzoek Cardiovasculair Reg. Med., Regenerative Medicine and Stem Cells, Ilahibaks, Nazma F., Ardisasmita, Arif I., Xie, Songpu, Gunnarsson, Anders, Brealey, Joseph, Vader, Pieter, de Jong, Olivier G., de Jager, Saskia, Dekker, Niek, Peacock, Ben, Schiffelers, Raymond M., Sluijter, Joost P.G., and Lei, Zhiyong

Published
2023

13. Extracellular vesicle‐mediated protein delivery to the liver.

Author

Ilahibaks, Nazma F., Roefs, Marieke T., Brans, Maike A. D., Blok, Christian Snijders, de Jager, Saskia C. A., Schiffelers, Raymond M., Vader, Pieter, Lei, Zhiyong, and Sluijter, Joost P. G.

Subjects
*LIVER proteins, *DRUG delivery systems, *INTRAVENOUS injections, *EXTRACELLULAR vesicles, *CELL communication
Abstract

Extracellular vesicles (EVs) are nanoscale particles that facilitate intercellular communication. They are regarded as a promising natural drug delivery system for transporting and delivering bioactive macromolecules to target cells. Recently, researchers have engineered EVs with FKBP12/FRB heterodimerization domains that interact with rapamycin to load and deliver exogenous proteins for both in vitro and in vivo applications. In this study, we examined the tissue distribution of EVs using near‐infrared fluorescent imaging. We evaluated the effectiveness of EV‐mediated delivery of Cre recombinase specifically to hepatocytes in the livers of Ai9 Cre‐loxP reporter mice. Intravenous injection resulted in more efficient Cre protein delivery to the liver than intraperitoneal injections. Depleting liver‐resident macrophages with clodronate‐encapsulated liposome pre‐treatment did not enhance EV‐mediated Cre delivery to hepatocytes. Moreover, we demonstrated that multiple intravenous injections of Cre‐EVs facilitated functional Cre delivery to hepatocytes. To the best of our knowledge, this is the first study to simultaneously investigate the tissue distribution of FKBP12/FRB‐engineered EVs and their subsequent intracellular protein delivery in Ai9 Cre‐loxP reporter mice. These insights can inform preclinical research and contribute to developing next‐generation EV‐based platforms for delivering therapeutic proteins or genome editing technologies targeting the liver. [ABSTRACT FROM AUTHOR]

Published
2023
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