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Gene therapy for chondral and osteochondral regeneration: is the future now?

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Abstract

Gene therapy might represent a promising strategy for chondral and osteochondral defects repair by balancing the management of temporary joint mechanical incompetence with altered metabolic and inflammatory homeostasis. This review analysed preclinical and clinical studies on gene therapy for the repair of articular cartilage defects performed over the last 10 years, focussing on expression vectors (non-viral and viral), type of genes delivered and gene therapy procedures (direct or indirect). Plasmids (non-viral expression vectors) and adenovirus (viral vectors) were the most employed vectors in preclinical studies. Genes delivered encoded mainly for growth factors, followed by transcription factors, anti-inflammatory cytokines and, less frequently, by cell signalling proteins, matrix proteins and receptors. Direct injection of the expression vector was used less than indirect injection of cells, with or without scaffolds, transduced with genes of interest and then implanted into the lesion site. Clinical trials (phases I, II or III) on safety, biological activity, efficacy, toxicity or bio-distribution employed adenovirus viral vectors to deliver growth factors or anti-inflammatory cytokines, for the treatment of osteoarthritis or degenerative arthritis, and tumour necrosis factor receptor or interferon for the treatment of inflammatory arthritis.

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Abbreviations

ACI:

Autologous chondrocytes implantation

ACPC:

Articular cartilage progenitor cells

ADSCs:

Adipose derived mesenchymal stem cells

BMP:

Bone morphogenetic protein

BMSCs:

Bone Marrow Derived Mesenchymal Stem Cells

bPEI-HA:

Branched poly(ethylenimine)-hyaluronic acid

CIA:

Collagen induced arthritis

COLL I:

Collagen I

COLL II:

Collagen II

Col2a1:

Collagen 2 alpha 1

COMP:

Cartilage oligomeric matrix protein

DBM:

Demineralized bone matrix

DCBM:

Decalcified cortical bone matrix

DRP:

DNase-resistant particles

ECM:

Extracellular matrix

FBs:

Fibroblasts

FGF-2:

Fibroblast growth factor 2

FLS:

Fibroblast-like synoviocytes

GAG:

Glycosaminoglycans

GDF-5:

Growth and differentiation factor 5

GFs:

Growth factor

GMP:

Good manufacture practice

HIV:

Human immunodeficiency virus

IFN-β:

Interferon-β

IGF-1:

Insulin-like growth factor 1

iHH:

Indian hedgehog homolog

IKDC:

International Knee Documentation Committee

IL10:

Interleukin 10

IL1ra:

Interleukin 1 receptor antagonist

MACI:

Matrix-induced autologous chondrocytes implantation

MDSCs:

Muscle-derived stem cells

MMP:

Metalloproteinase

MSCs:

MESENCHYMAL Stem cells

OA:

Osteoarthritis

PGA:

Polyglycolic acid

PLA:

Polylactic acid

PLGA:

Poly(lactic-co-glycolide)

PU:

Polyurethane

RA:

Rheumatoid arthritis

rAAV:

Recombinant adeno-associated viral vector

RUNX2:

Runt-related transcription factor 2

scAAV:

Self-complementary AAV

sFlt-1:

Soluble Fms-related tyrosine kinase 1

SOX:

Sex-determining Region Y -related High Mobility Group box

TCP:

Tricalcium phosphate

TFs:

Transcription factors

TGF-β:

Transforming growth factor β

TNFR:Fc:

Human tumor necrosis factor receptor immunoglobulin (IgG1) Fc fusion

VAS:

Visual analogue scale

VEGF:

Vascular endothelial growth factor

ZNF145:

Zinc-finger protein 145

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Acknowledgements

This study has been developed with the contribution of the National Operational Programme for Research and Competitiveness 2007–2013—PONa03_00011 “Potenziamento strutturale di una rete di eccellenza per la ricerca clinica sulla terapia personalizzata in oncologia e in medicina rigenerativa”.

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Authors and Affiliations

  1. Rizzoli Orthopedic Institute, Bologna, Italy

    Daniele Bellavia, V. Carina, V. Costa, L. Raimondi & A. De Luca

  2. Innovative Technology Platforms for Tissue Engineering, Theranostic and Oncology, Rizzoli Orthopaedic Institute, Via Divisi 83, 90133, Palermo, Italy

    Daniele Bellavia, V. Carina, V. Costa, L. Raimondi, A. De Luca & G. Giavaresi

  3. Laboratory of Preclinical and Surgical Studies, Rizzoli Orthopaedic Institute, Bologna, Italy

    F. Veronesi, M. Fini & G. Giavaresi

  4. Biology and Genetics Unit, Department of Biopathology and Medical Biotechnology, University of Palermo, Palermo, Italy

    R. Alessandro

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  1. Daniele Bellavia
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  2. F. Veronesi
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  3. V. Carina
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Correspondence to Daniele Bellavia.

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Bellavia, D., Veronesi, F., Carina, V. et al. Gene therapy for chondral and osteochondral regeneration: is the future now?. Cell. Mol. Life Sci. 75, 649–667 (2018). https://doi.org/10.1007/s00018-017-2637-3

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  • DOI: https://doi.org/10.1007/s00018-017-2637-3

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