Open Access

Pharmaceutics, volume 12, issue 12, pages 1231

Therapeutic Angiogenesis by a “Dynamic Duo”: Simultaneous Expression of HGF and VEGF165 by Novel Bicistronic Plasmid Restores Blood Flow in Ischemic Skeletal Muscle

Slobodkina Ekaterina ^{1, 2}

Boldyreva Maria ^{3, 4}

Karagyaur Maxim ^{1, 2}

Eremichev Roman ¹

Alexandrushkina Natalia ^{1, 2}

Balabanyan Vadim ^{1, 2}

Akopyan Zhanna ^{1, 2}

Parfyonova Yelena V. ^{2, 3}

Tkachuk Vsevolod ^{1, 2, 3}

Makarevich Pavel I ^{1, 2}

Hide authors affiliations Show authors affiliations: 4 affiliations

Institute for Regenerative Medicine, Medical Research and Education Centre, Lomonosov Moscow State University, 119192 Moscow, Russia |

Faculty of Medicine, Lomonosov Moscow State University, 117192 Moscow, Russia |

National Medical Research Center of Cardiology Russian Ministry of Health, 121552 Moscow, Russia |

⁴

Faculty of Biology and Biotechnology, National Research University Higher School of Economics (HSE), 109028 Moscow, Russia |

Publication type: Journal Article

Publication date: 2020-12-18

Multidisciplinary Digital Publishing Institute (MDPI)

Journal: Pharmaceutics

Quartile SCImago

Quartile WOS

Impact factor: 5.4

ISSN: 19994923

DOI: 10.3390/pharmaceutics12121231

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Pharmaceutical Science

Abstract

Therapeutic angiogenesis is a promising strategy for relief of ischemic conditions, and gene delivery was used to stimulate blood vessels’ formation and growth. We have previously shown that intramuscular injection of a mixture containing plasmids encoding vascular endothelial growth factor (VEGF)165 and hepatocyte growth factor (HGF) leads to restoration of blood flow in mouse ischemic limb, and efficacy of combined delivery was superior to each plasmid administered alone. In this work, we evaluated different approaches for co-expression of HGF and VEGF165 genes in a panel of candidate plasmid DNAs (pDNAs) with internal ribosome entry sites (IRESs), a bidirectional promoter or two independent promoters for each gene of interest. Studies in HEK293T culture showed that all plasmids provided synthesis of HGF and VEGF165 proteins and stimulated capillary formation by human umbilical vein endothelial cells (HUVEC), indicating the biological potency of expressed factors. Tests in skeletal muscle explants showed a dramatic difference and most plasmids failed to express HGF and VEGF165 in a significant quantity. However, a bicistronic plasmid with two independent promoters (cytomegalovirus (CMV) for HGF and chicken b-actin (CAG) for VEGF165) provided expression of both grow factors in skeletal muscle at an equimolar ratio. Efficacy tests of bicistronic plasmid were performed in a mouse model of hind limb ischemia. Intramuscular administration of plasmid induced significant restoration of perfusion compared to an empty vector and saline. These findings were supported by increased CD31+ capillary density in animals that received pHGF/VEGF. Overall, our study reports a first-in-class candidate gene therapy drug to deliver two pivotal angiogenic growth factors (HGF and VEGF165) with properties that provide basis for future development of treatment for an unmet medical need—peripheral artery disease and associated limb ischemia.

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Cells	Cells, 2, 28.57% Cells 2 publications, 28.57%
Frontiers in Molecular Biosciences	Frontiers in Molecular Biosciences, 1, 14.29% Frontiers in Molecular Biosciences 1 publication, 14.29%
International Journal of Molecular Sciences	International Journal of Molecular Sciences, 1, 14.29% International Journal of Molecular Sciences 1 publication, 14.29%
Acta Biomaterialia	Acta Biomaterialia, 1, 14.29% Acta Biomaterialia 1 publication, 14.29%
Journal of Ethnopharmacology	Journal of Ethnopharmacology, 1, 14.29% Journal of Ethnopharmacology 1 publication, 14.29%
Frontiers in Pharmacology	Frontiers in Pharmacology, 1, 14.29% Frontiers in Pharmacology 1 publication, 14.29%
	1 2

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	1 2 3
Multidisciplinary Digital Publishing Institute (MDPI)	Multidisciplinary Digital Publishing Institute (MDPI), 3, 42.86% Multidisciplinary Digital Publishing Institute (MDPI) 3 publications, 42.86%
Frontiers Media S.A.	Frontiers Media S.A., 2, 28.57% Frontiers Media S.A. 2 publications, 28.57%
Elsevier	Elsevier, 2, 28.57% Elsevier 2 publications, 28.57%
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Slobodkina E. et al. Therapeutic Angiogenesis by a “Dynamic Duo”: Simultaneous Expression of HGF and VEGF165 by Novel Bicistronic Plasmid Restores Blood Flow in Ischemic Skeletal Muscle // Pharmaceutics. 2020. Vol. 12. No. 12. p. 1231.

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Slobodkina E., Boldyreva M., Karagyaur M., Eremichev R., Alexandrushkina N., Balabanyan V., Akopyan Z., Parfyonova Y. V., Tkachuk V., Makarevich P. I. Therapeutic Angiogenesis by a “Dynamic Duo”: Simultaneous Expression of HGF and VEGF165 by Novel Bicistronic Plasmid Restores Blood Flow in Ischemic Skeletal Muscle // Pharmaceutics. 2020. Vol. 12. No. 12. p. 1231.

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TY - JOUR

DO - 10.3390/pharmaceutics12121231

UR - https://doi.org/10.3390%2Fpharmaceutics12121231

TI - Therapeutic Angiogenesis by a “Dynamic Duo”: Simultaneous Expression of HGF and VEGF165 by Novel Bicistronic Plasmid Restores Blood Flow in Ischemic Skeletal Muscle

T2 - Pharmaceutics

AU - Slobodkina, Ekaterina

AU - Karagyaur, Maxim

AU - Eremichev, Roman

AU - Alexandrushkina, Natalia

AU - Balabanyan, Vadim

AU - Akopyan, Zhanna

AU - Tkachuk, Vsevolod

AU - Boldyreva, Maria

AU - Parfyonova, Yelena V.

AU - Makarevich, Pavel I

PY - 2020

DA - 2020/12/18 00:00:00

PB - Multidisciplinary Digital Publishing Institute (MDPI)

SP - 1231

IS - 12

VL - 12

SN - 1999-4923

ER -

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@article{2020_Slobodkina,

author = {Ekaterina Slobodkina and Maxim Karagyaur and Roman Eremichev and Natalia Alexandrushkina and Vadim Balabanyan and Zhanna Akopyan and Vsevolod Tkachuk and Maria Boldyreva and Yelena V. Parfyonova and Pavel I Makarevich},

title = {Therapeutic Angiogenesis by a “Dynamic Duo”: Simultaneous Expression of HGF and VEGF165 by Novel Bicistronic Plasmid Restores Blood Flow in Ischemic Skeletal Muscle},

journal = {Pharmaceutics},

year = {2020},

volume = {12},

publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},

month = {dec},

url = {https://doi.org/10.3390%2Fpharmaceutics12121231},

number = {12},

pages = {1231},

doi = {10.3390/pharmaceutics12121231}

}

MLA

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Slobodkina, Ekaterina, et al. “Therapeutic Angiogenesis by a “Dynamic Duo”: Simultaneous Expression of HGF and VEGF165 by Novel Bicistronic Plasmid Restores Blood Flow in Ischemic Skeletal Muscle.” Pharmaceutics, vol. 12, no. 12, Dec. 2020, p. 1231. https://doi.org/10.3390%2Fpharmaceutics12121231.

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Publisher

Multidisciplinary Digital Publishing Institute (MDPI)

Journal

Pharmaceutics

Quartile SCImago

Quartile WOS

Impact factor

5.4

ISSN

19994923 (Print)

Labs

Laboratory of Gene Cell Therapy

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