Concepts in gene therapy for cartilage repair

Abstract

Once articular cartilage is injured, it has a very limited capacity for self repair. Although current surgical therapeutic procedures for 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 various 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 anti-inflammatory mediators. Gene transfer targeted at 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.

Figure 1

Gene transfer approaches for the treatment of cartilage defects. (A) For in vivo gene transfer, free vector is either injected directly into the joint space, or incorporated into a biologically compatible matrix before implantation into a cartilage defect (gene activated matrix (GAM) implantation). Resident cells that encounter the vector acquire the desired gene, and genetically modified cells secrete the transgene products that influence the regeneration of articular cartilage. (B) Abbreviated ex vivo genetically enhanced tissue engineering to treat cartilage defects. A vector is incorporated into the matrix together with cells that are harvested at the same operative setting, such as stromal cells from bone marrow aspirates. (C) Ex vivo genenetically enhanced tissue engineering for cartilage repair involves the harvest and expansion of target cells in vitro, which are subsequently infected with the desired vector. The transduced cells then may be selected, and seeded into a biological matrix before the construct is transplanted into a cartilage defect. Depending on the approach chosen, ubiquitous or local transgene expression (TGE) is induced by the genetically modified cells, and the gene products could beneficially influence cartilage repair by either transplanted cells as well as those that may migrate into the defect site.