Gene-based approaches for the repair of articular cartilage

Trippel, Stephen B.; Ghivizzani, S. C.; Nixon, A. J.

doi:10.1038/sj.gt.3302201

Cited by 125 publications

(103 citation statements)

References 93 publications

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“…Of particular interest are morphogens and transcription factors that promote differentiation along chondrogenic lineages, growth factors that promote matrix synthesis, inhibitors of osteogenic or hypertrophic differentiation, antagonists that inhibit apoptosis, senescence or responses to catabolic cytokines ( Table 1). Several of these substances have shown promise in animal models of cartilage repair and regeneration, but their clinical application is hindered by delivery problems [103,164,171]. Due to the limited half-lives of many proteins in vivo, they are particularly difficult to administer to sites of cartilage damage at therapeutic concentrations and for sustained periods of time.…”

Section: Candidate Gene Productsmentioning

confidence: 99%

“…Due to the limited half-lives of many proteins in vivo, they are particularly difficult to administer to sites of cartilage damage at therapeutic concentrations and for sustained periods of time. Localized delivery of these agents without involvement of non-target organs has also proven to be problematic [164,171]. We suggest that these limitations may be overcome by adapting appropriate gene transfer technologies.…”

Section: Candidate Gene Productsmentioning

confidence: 99%

“…We suggest that these limitations may be overcome by adapting appropriate gene transfer technologies. In particular, it should be possible to develop techniques for transferring therapeutic genes encoding the necessary gene products to cells at the sites of injury or disease, for sustained local expression at high levels with minimal collateral exposure of non-target tissues [164,171]. In this manner, the proteins of interest are synthesized locally by cells and are presented to the microenvironment in a natural fashion.…”

Section: Candidate Gene Productsmentioning

confidence: 99%

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Concepts in gene therapy for cartilage repair

Steinert

Nöth

Tuan

2008

Injury

141

117

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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.

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Section: Candidate Gene Productsmentioning

confidence: 99%

Section: Candidate Gene Productsmentioning

confidence: 99%

Section: Candidate Gene Productsmentioning

confidence: 99%

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Concepts in gene therapy for cartilage repair

Steinert

Nöth

Tuan

2008

Injury

141

117

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“…Since P3 cells permitted a cell expansion ratio of E12-fold (data not shown), the use of autologous cells is made possible with this approach. It is noteworthy that, although other growth factors such as transforming growth factor b1 41 and insulin-like growth factor-I 42 enhanced cartilage matrix production from P0 or P1 cells and promoted cartilage repair in vitro or in vivo (for review, see Trippel et al, 1 Cucchiarini and Madry, 3 Lieberman et al, 4 Huard et al 43 ), the delivery of genes encoding either one of these two factors failed to pronouncedly reverse the dedifferentiation of P3 chondrocytes despite efficient transgene expression. 44 In this regard, BMP-2 may be a more potent inducer to restore the dedifferentiation.…”

Section: Discussionmentioning

confidence: 99%

“…To ameliorate the cartilage repair, cell therapy and gene transfer have converged in recent years, by which therapeutic genes can be introduced by in vivo gene delivery. Alternatively, cartilage repair can be augmented via ex vivo gene transfer into freshly isolated cells and subsequent cell implantation (for review see Trippel et al, 1 Gelse and Schneider, 2 Cucchiarini and Madry, 3 Lieberman et al, 4 Saraf and Mikos 5 ), by which the expressed gene products can promote tissue regeneration in vivo. The genes may be delivered with retrovirus, lentivirus, adenovirus, adeno-associated virus, herpes simplex virus or other nonviral vectors.…”

Section: Introductionmentioning

confidence: 99%

Combination of baculovirus-expressed BMP-2 and rotating-shaft bioreactor culture synergistically enhances cartilage formation

et al. 2007

Gene Ther

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Baculovirus is an emerging gene delivery vector, thanks to a number of unique advantages. Herein, we genetically modified the rabbit articular chondrocytes with a recombinant baculovirus (Bac-CB) encoding bone morphogenetic protein-2 (BMP-2), which conferred high level BMP-2 expression and triggered the re-differentiation of dedifferentiated third passage (P3) chondrocytes in the monolayer culture. The transduced and mock-transduced P3 cells were seeded into porous scaffolds and cultured in either the dishes or the rotating-shaft bioreactor (RSB), a novel bioreactor imparting a dynamic, two-phase culture environment. Neither mocktransduced constructs in the RSB culture nor the Bac-CBtransduced constructs in the static culture grew into uniform cartilaginous tissues. Only the Bac-CB-transduced constructs cultured in the RSB for 3 weeks resulted in cartilaginous tissues with hyaline appearance, uniform cell distribution, cartilage-specific gene expression and considerably enhanced cartilage-specific extracellular matrix deposition, as determined by histological staining, reverse transcription-PCR analyses and biochemical assays. This is the first study demonstrating that combination of baculovirusmediated growth factor expression and RSB culture synergistically enhanced in vitro creation of cartilaginous tissues from dedifferentiated chondrocytes. Since baculovirus transduction is generally considered safe, this approach represents a viable alternative to stimulate the formation of engineered cartilage in a more cost-effective way than the growth factor supplementation.

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Tissue‐Engineered Cartilage

Pagnotto

Chu

2006

Wiley Encyclopedia of Biomedical Engineering

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The goal of cartilage tissue engineering is to recreate functional articular cartilage. The tissue must be able to fill chondral defects while maintaining the unique biomechanical characteristics that make articular cartilage functional. The goal may be accomplished either by inducing native repair cells to regenerate or through ex vivo techniques where cells are obtained from a patient and use to develop cartilage or pre‐cartilaginous constructs in the laboratory and then the constructs are surgically implanted back into the patient. As this chapter will demonstrate, extensive research continues to examine nearly every facet of cartilage tissue engineering.

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Gene-based approaches for the repair of articular cartilage

Cited by 125 publications

References 93 publications

Concepts in gene therapy for cartilage repair

Concepts in gene therapy for cartilage repair

Combination of baculovirus-expressed BMP-2 and rotating-shaft bioreactor culture synergistically enhances cartilage formation

Tissue‐Engineered Cartilage

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