Preclinical evaluation of mesenchymal stem cells overexpressing VEGF to treat critical limb ischemia

Julie R. Beegle, Nataly Lessa Magner, Stefanos Kalomoiris, Aja Harding, Ping Zhou, Catherine Nacey, Jeannine Logan White, Karen Pepper, William Gruenloh, Geralyn Annett, Jan Nolta, Fernando A Fierro

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Numerous clinical trials are utilizing mesenchymal stem cells (MSC) to treat critical limb ischemia, primarily for their ability to secrete signals that promote revascularization. These cells have demonstrated clinical safety, but their efficacy has been limited, possibly because these paracrine signals are secreted at subtherapeutic levels. In these studies the combination of cell and gene therapy was evaluated by engineering MSC with a lentivirus to overexpress vascular endothelial growth factor (VEGF). To achieve clinical compliance, the number of viral insertions was limited to 1–2 copies/cell and a constitutive promoter with demonstrated clinical safety was used. MSC/VEGF showed statistically significant increases in blood flow restoration as compared with sham controls, and more consistent improvements as compared with nontransduced MSC. Safety of MSC/VEGF was assessed in terms of genomic stability, rule-out tumorigenicity, and absence of edema or hemangiomas in vivo. In terms of retention, injected MSC/VEGF showed a steady decline over time, with a very small fraction of MSC/VEGF remaining for up to 4.5 months. Additional safety studies completed include absence of replication competent lentivirus, sterility tests, and absence of VSV-G viral envelope coding plasmid. These preclinical studies are directed toward a planned phase 1 clinical trial to treat critical limb ischemia.

Original languageEnglish (US)
Pages (from-to)16053
Number of pages1
JournalMolecular Therapy - Methods and Clinical Development
Volume3
DOIs
StatePublished - Mar 16 2016

Fingerprint

Mesenchymal Stromal Cells
Vascular Endothelial Growth Factor A
Ischemia
Extremities
Safety
Lentivirus
Clinical Trials, Phase I
Genomic Instability
Hemangioma
Cell- and Tissue-Based Therapy
Genetic Therapy
Infertility
Compliance
Edema
Plasmids
Clinical Trials

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine

Cite this

Preclinical evaluation of mesenchymal stem cells overexpressing VEGF to treat critical limb ischemia. / Beegle, Julie R.; Magner, Nataly Lessa; Kalomoiris, Stefanos; Harding, Aja; Zhou, Ping; Nacey, Catherine; White, Jeannine Logan; Pepper, Karen; Gruenloh, William; Annett, Geralyn; Nolta, Jan; Fierro, Fernando A.

In: Molecular Therapy - Methods and Clinical Development, Vol. 3, 16.03.2016, p. 16053.

Research output: Contribution to journalArticle

Beegle, Julie R. ; Magner, Nataly Lessa ; Kalomoiris, Stefanos ; Harding, Aja ; Zhou, Ping ; Nacey, Catherine ; White, Jeannine Logan ; Pepper, Karen ; Gruenloh, William ; Annett, Geralyn ; Nolta, Jan ; Fierro, Fernando A. / Preclinical evaluation of mesenchymal stem cells overexpressing VEGF to treat critical limb ischemia. In: Molecular Therapy - Methods and Clinical Development. 2016 ; Vol. 3. pp. 16053.
@article{6951e0998a3443f8b07e2ff692bebfd4,
title = "Preclinical evaluation of mesenchymal stem cells overexpressing VEGF to treat critical limb ischemia",
abstract = "Numerous clinical trials are utilizing mesenchymal stem cells (MSC) to treat critical limb ischemia, primarily for their ability to secrete signals that promote revascularization. These cells have demonstrated clinical safety, but their efficacy has been limited, possibly because these paracrine signals are secreted at subtherapeutic levels. In these studies the combination of cell and gene therapy was evaluated by engineering MSC with a lentivirus to overexpress vascular endothelial growth factor (VEGF). To achieve clinical compliance, the number of viral insertions was limited to 1–2 copies/cell and a constitutive promoter with demonstrated clinical safety was used. MSC/VEGF showed statistically significant increases in blood flow restoration as compared with sham controls, and more consistent improvements as compared with nontransduced MSC. Safety of MSC/VEGF was assessed in terms of genomic stability, rule-out tumorigenicity, and absence of edema or hemangiomas in vivo. In terms of retention, injected MSC/VEGF showed a steady decline over time, with a very small fraction of MSC/VEGF remaining for up to 4.5 months. Additional safety studies completed include absence of replication competent lentivirus, sterility tests, and absence of VSV-G viral envelope coding plasmid. These preclinical studies are directed toward a planned phase 1 clinical trial to treat critical limb ischemia.",
author = "Beegle, {Julie R.} and Magner, {Nataly Lessa} and Stefanos Kalomoiris and Aja Harding and Ping Zhou and Catherine Nacey and White, {Jeannine Logan} and Karen Pepper and William Gruenloh and Geralyn Annett and Jan Nolta and Fierro, {Fernando A}",
year = "2016",
month = "3",
day = "16",
doi = "10.1038/mtm.2016.53",
language = "English (US)",
volume = "3",
pages = "16053",
journal = "Molecular Therapy - Methods and Clinical Development",
issn = "2329-0501",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Preclinical evaluation of mesenchymal stem cells overexpressing VEGF to treat critical limb ischemia

AU - Beegle, Julie R.

AU - Magner, Nataly Lessa

AU - Kalomoiris, Stefanos

AU - Harding, Aja

AU - Zhou, Ping

AU - Nacey, Catherine

AU - White, Jeannine Logan

AU - Pepper, Karen

AU - Gruenloh, William

AU - Annett, Geralyn

AU - Nolta, Jan

AU - Fierro, Fernando A

PY - 2016/3/16

Y1 - 2016/3/16

N2 - Numerous clinical trials are utilizing mesenchymal stem cells (MSC) to treat critical limb ischemia, primarily for their ability to secrete signals that promote revascularization. These cells have demonstrated clinical safety, but their efficacy has been limited, possibly because these paracrine signals are secreted at subtherapeutic levels. In these studies the combination of cell and gene therapy was evaluated by engineering MSC with a lentivirus to overexpress vascular endothelial growth factor (VEGF). To achieve clinical compliance, the number of viral insertions was limited to 1–2 copies/cell and a constitutive promoter with demonstrated clinical safety was used. MSC/VEGF showed statistically significant increases in blood flow restoration as compared with sham controls, and more consistent improvements as compared with nontransduced MSC. Safety of MSC/VEGF was assessed in terms of genomic stability, rule-out tumorigenicity, and absence of edema or hemangiomas in vivo. In terms of retention, injected MSC/VEGF showed a steady decline over time, with a very small fraction of MSC/VEGF remaining for up to 4.5 months. Additional safety studies completed include absence of replication competent lentivirus, sterility tests, and absence of VSV-G viral envelope coding plasmid. These preclinical studies are directed toward a planned phase 1 clinical trial to treat critical limb ischemia.

AB - Numerous clinical trials are utilizing mesenchymal stem cells (MSC) to treat critical limb ischemia, primarily for their ability to secrete signals that promote revascularization. These cells have demonstrated clinical safety, but their efficacy has been limited, possibly because these paracrine signals are secreted at subtherapeutic levels. In these studies the combination of cell and gene therapy was evaluated by engineering MSC with a lentivirus to overexpress vascular endothelial growth factor (VEGF). To achieve clinical compliance, the number of viral insertions was limited to 1–2 copies/cell and a constitutive promoter with demonstrated clinical safety was used. MSC/VEGF showed statistically significant increases in blood flow restoration as compared with sham controls, and more consistent improvements as compared with nontransduced MSC. Safety of MSC/VEGF was assessed in terms of genomic stability, rule-out tumorigenicity, and absence of edema or hemangiomas in vivo. In terms of retention, injected MSC/VEGF showed a steady decline over time, with a very small fraction of MSC/VEGF remaining for up to 4.5 months. Additional safety studies completed include absence of replication competent lentivirus, sterility tests, and absence of VSV-G viral envelope coding plasmid. These preclinical studies are directed toward a planned phase 1 clinical trial to treat critical limb ischemia.

UR - http://www.scopus.com/inward/record.url?scp=85015202329&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85015202329&partnerID=8YFLogxK

U2 - 10.1038/mtm.2016.53

DO - 10.1038/mtm.2016.53

M3 - Article

VL - 3

SP - 16053

JO - Molecular Therapy - Methods and Clinical Development

JF - Molecular Therapy - Methods and Clinical Development

SN - 2329-0501

ER -