Concepts in gene therapy for cartilage repair

Abstract

SummaryOnce articular cartilage is injured, it has a very limited capacity for self-repair. Although current surgical therapeutic procedures to cartilage repair are clinically useful, they cannot restore a normal articular surface. Current research offers a growing number of bioactive reagents, including proteins and nucleic acids, that may be used to augment different aspects of the repair process. As these agents are difficult to administer effectively, gene transfer approaches are being developed to provide their sustained synthesis at sites of repair.To augment regeneration of articular cartilage, therapeutic genes can be delivered to the synovium, or directly to the cartilage lesion. Gene delivery to the cells of the synovial lining is generally considered more suitable for chondroprotective approaches, based on the expression of antiinflammatory mediators. Gene transfer targeted to cartilage defects can be achieved by either direct vector administration to cells located at or surrounding the defects, or by transplantation of genetically modified chondrogenic cells into the defect. Several studies have shown that exogenous cDNAs encoding growth factors can be delivered locally to sites of cartilage damage, where they are expressed at therapeutically relevant levels. Furthermore, data is beginning to emerge indicating, that efficient delivery and expression of these genes is capable of influencing a repair response toward the synthesis of a more hyaline cartilage repair tissue in vivo. This review presents the current status of gene therapy for cartilage healing and highlights some of the remaining challenges.

Bone and Cartilage from Stem Cells: Growth Optimalization and Stabilization of Cell Phenotypes

“…The concepts of gene therapy for cartilage repair have been thoroughly reviewed by Steinert et al (Steinert, Noth et al 2008). Approaches mentioned are stimulation of chondrogenic differentiation (using TGF s, BMPs, WNT, SMADs, SOX9, Brachyury), stimulation of cartilage matrix synthesis and/or cell proliferation (TGF s, BMPs, IGF-1, PDGF, type 2 Collagen minigene, COMP, GlcAT-1), inhibition of osteogenesis/hypertrophy growth factors (Noggin, Chordin, PTHrP, SMAD6,7), the use of anti-inflammatory agents (IL-1 blockage, TNF -inhibition, MMP-inhibition), senescence inhibition, and inhibition of apoptosis (Saraf and Mikos 2006;Steinert, Noth et al 2008).…”

“…Approaches mentioned are stimulation of chondrogenic differentiation (using TGF s, BMPs, WNT, SMADs, SOX9, Brachyury), stimulation of cartilage matrix synthesis and/or cell proliferation (TGF s, BMPs, IGF-1, PDGF, type 2 Collagen minigene, COMP, GlcAT-1), inhibition of osteogenesis/hypertrophy growth factors (Noggin, Chordin, PTHrP, SMAD6,7), the use of anti-inflammatory agents (IL-1 blockage, TNF -inhibition, MMP-inhibition), senescence inhibition, and inhibition of apoptosis (Saraf and Mikos 2006;Steinert, Noth et al 2008). The delivery systems for chondrogenic genes show many common features to the ones described for enhancing osteoblastogenesis (see above) (Saraf and Mikos 2006;Betz 2008).…”

Gene Therapy Outcomes in Experimental Models of Inflammatory Arthritis

“…Over the past 7 years or so a considerable amount of research activity has been devoted to the development of gene therapeutic strategies that have resulted in 1) neutralization of the effects of IL-1 with an IL-1 receptor antagonist (IL-1-Ra) expression plasmid (Kim et al;; 2) elevating the levels of Th2 cytokines exemplified by IL-10 (Traister & Hirsh, 2008), IL-4 (Kageyama et al, 2004) and IL-13 (Nabbe et al, 2005); 3) suppression of Th1 cytokines such as IL-18 (Smeets et al, 2003) and IL-17, the latter by modification of the indoleamine 2,3-dioxygenase pathway (Chen et al, 2011); 4) blunting of TNF--stimulated signaling (Denys et al, 2010) and interferon-activity (Adriaansen et al;; 5) up-regulation of the protein inhibitor of activated STAT1 (PIAS) activity by stimulating the capacity of small ubiquitin-like modifier E3 ligase (SUMO E3) to alter inhibitor of κB kinase (IKK ) phosphorylation (Liu & Shuai, 2008); 6) gene transfer of genetically modified chondrocytes into cartilage defects to promote cartilage regeneration (Steinert et al, 2008); and 7) promotion of adiponectin gene expression (Ebina et al, 2009). In addition, because new blood vessel formation is also intimately involved with perpetuating the chronic state of inflammation associated with RA, experimental gene therapy strategies designed to suppress the activity of pro-angiogenesis factors such as vascular endothelial growth factor (VEGF) (Afuwape et al, 2003) and Tie-2 (Chen et al, 2005) have also been earnestly pursued.…”

Growth Factor Delivery Through Self-assembling Peptide Scaffolds

“…Growth factors including transforming growth factor-b1 (TGF-b1), insulin-like growth factor-1 (IGF-1), and members of the growth differentiation factor (GDF) and bone morphogenetic protein (BMP) families are important in inducing repair, attracting migration of repair cells, and stimulating chondrogenesis, proliferation, and production of matrix [4,46,47]. Because growth factors act on multiple tissues and can have detrimental side effects if applied systemically, local delivery is necessary.…”