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Changing the Course of Peripheral Arterial Disease Using Adult Stem Progenitor Cells

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Stem Cell Therapy for Vascular Diseases

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Abstract

Lower extremity arterial disease affects more than 200 × 10e6 people worldwide causing Critical Limb Ischemia (CLI), also referred to as chronic limb-threatening ischemia (CLTI) a life-threatening disease and the major cause of ischemic amputation. For nonrevascularizable patients, the outlook is bleak and novel therapies are needed. This chapter discusses new approaches including gene therapy and stem/progenitor cell (SPC)-based therapies, including autologous bone marrow-derived cells (BM), MB-mononuclear cells (BM-MNC), mesenchymal stem cells (MSC), mobilized bone marrow cell (PB-MNC), allogeneic cells and ex vivo expanded or activated/differentiated cell products. A preliminary first-in-human trial of a novel treatment is presented that combines immune cell therapy and a stepwise activation and differentiation of SPC. Cells from a standard blood draw (with no pretreatment or mobilization) are transformed, within a day, into a therapeutic product (BGC101) composed of endothelial progenitor cells (EPCs), SPCs, dendritic cells (DCs), and T helper cells. BGC101 was found safe and effective in stabilizing and reversing the course of CLI. Controlled studies on a larger population are planned to evaluate this new concept.

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Abbreviations

ABI:

Ankle-brachial Index

ACE:

Angiotensin-converting enzyme

AcLDL:

Acetylated low-density lipoprotein

ACP:

Angiogenic cell precursor

AE:

Adverse events

AFS:

Amputation-free survival

ATMP:

Advanced therapy medicinal products

AP:

Ankle pressure

BM:

Bone marrow

CFA:

Common femoral artery

CLI:

Critical Limb Ischemia

CLTI:

chronic limb-threatening ischemia

CTCAE:

Common Terminology Criteria for Adverse Events

CPK:

Creatine phosphokinase

CV:

Cardiovascular

DC:

Dendritic cell

Del-1 and DELTA 1:

Developmentally regulated endothelial locus

DSMB:

Data and Safety Monitoring Board

EC:

Endothelial cells

EnEPC:

Enriched endothelial progenitor cells

EPC:

Endothelial progenitor cells

ESC:

European Society for Cardiology

EVT:

Endovascular therapy

FGF :

Fibroblast growth factor

FIH:

First in human

GVHD:

Graft-versus-host disease

GSV:

Great saphenous vein

G-CSF:

Granulocyte colony-stimulating factor

GCP:

Good clinical practice

GMP:

Good manufacturing practice

GTP:

Good tissue practice

Hg:

Hemoglobin

HGF:

Hepatocyte growth factor

HIF:

Hypoxia inducible factor

HSPC:

Hematopoietic stem/progenitor cells

IA:

Intra-arterial

IC:

Intermittent claudication

ICH:

International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use

IL-10:

Interleukin-10

IM:

Intramuscular

IV:

Intravenous

LEAD:

Lower extremity arterial disease

LOCF:

Last observation carried forward

MedDRA:

Medical Dictionary for Regulatory Activities

MI:

Myocardial infarction

MNC:

Mononuclear cells

MSC:

Mesenchymal stem cells

NIH:

National Institutes of Health

NO:

Nitric oxide

PAD:

Peripheral artery disease

PBMC:

Peripheral blood mononuclear cell

PB-MNC:

Peripheral blood-derived mononuclear cells

PI:

Principal investigator

PTA:

Percutaneous transluminal angioplasty

PVR :

Pulse volume recording

QoL:

Quality of life

RCT:

Randomized controlled trial

RNA:

Ribonucleic acids

SAE:

Severe adverse effect

SOC :

System organ class

SPC:

Stem/progenitor cells

TASC:

Trans-Atlantic Inter-Society Consensus

TBI:

Toe-brachial index

TcPO2:

Transcutaneous oxygen pressure

TGF-β:

Transforming growth factor beta

TP:

Toe pressure

TTF:

Treatment failure

Ulex:

Plant Ulex europaeus

VAS:

Visual Analogue Scale

VascuQol:

Vascular Quality of Life

VEGF:

Vascular endothelial growth factor

WBC:

White blood cells

WIfI:

Wound, Ischemia, and foot Infection

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Authors and Affiliations

  1. Sanz Medical Center, Laniado Hospital, Netanya, Israel

    Mark Niven, Shlomo Baytner, Roman Liberson, Shlomo Bulvik & Michael Belkin

  2. Rabin Medical center, Tel Aviv University, Tel Aviv, Israel

    Galit Sivak

  3. BioGenCell, Ltd., Laniado Hospital, Netanya, Israel

    Yael Porat

  4. Cohen’s Children’s Medical Center, New Hyde Park, NY, USA

    Michael Frogel

  5. Tel Aviv University, Tel Aviv, Israel

    Louis Shenkman & Michael Belkin

  6. Albert Einstein College of Medicine, Bronx, NY, USA

    Martin Grajower

  7. NYU-Langone Medical Center, New York, NY, USA

    Frank Veith

  8. The Cleveland Clinic, Cleveland, OH, USA

    Frank Veith

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  1. Mark Niven
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  11. Michael Belkin
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Correspondence to Yael Porat .

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Editors and Affiliations

  1. Department of Surgery, Vascular Surgery Section, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

    Tulio Pinho Navarro

  2. Postgraduate Program in Sciences Applied to Surgery, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

    Lara Lellis Navarro Minchillo Lopes

  3. Vascular Biology and Therapeutics Program and the Departments of Surgery and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA

    Alan Dardik

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Niven, M. et al. (2021). Changing the Course of Peripheral Arterial Disease Using Adult Stem Progenitor Cells. In: Navarro, T.P., Minchillo Lopes, L.L.N., Dardik, A. (eds) Stem Cell Therapy for Vascular Diseases. Springer, Cham. https://doi.org/10.1007/978-3-030-56954-9_12

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