Gene therapy for cartilage defects

Abstract

Focal defects of articular cartilage are an unsolved problem in clinical orthopaedics. These lesions do not heal spontaneously and no treatment leads to complete and durable cartilage regeneration. Although the concept of gene therapy for cartilage damage appears elegant and straightforward, current research indicates that an adaptation of gene transfer techniques to the problem of a circumscribed cartilage defect is required in order to successfully implement this approach. In particular, the localised delivery into the defect of therapeutic gene constructs is desirable. Current strategies aim at inducing chondrogenic pathways in the repair tissue that fills such defects. These include the stimulation of chondrocyte proliferation, maturation, and matrix synthesis via direct or cell transplantation-mediated approaches. Among the most studied candidates, polypeptide growth factors have shown promise to enhance the structural quality of the repair tissue. A better understanding of the basic scientific aspects of cartilage defect repair, together with the identification of additional molecular targets and the development of improved gene-delivery techniques, may allow a clinical translation of gene therapy for cartilage defects. The first experimental steps provide reason for cautious optimism.

Restoration of the extracellular matrix in human osteoarthritic articular cartilage by overexpression of the transcription factor SOX9

“…Vectors based on AAV might be advantageous to achieving this goal because they have the unique ability to mediate both efficient and stable transgene expression throughout the entire depth of cartilage (23,24), in marked contrast with the properties of other classes of vectors (27). In the present study, we evaluated the ability of rAAV-mediated SOX9 overexpression to restore the cartilage matrix in human OA cartilage as compared with normal cartilage.…”

“…In addition, rAAV exhibit a reduced immunogenicity due to the complete removal of the viral protein coding sequences in the recombinant genome. These features are in marked contrast with the properties of other classes of vectors (27), such as retroviral vectors, which necessitate the division of the target cells (28), or adenoviral vectors, which generally mediate only shortterm transgene expression (29).…”

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

“…Although genetic modification of chondrocytes or chondroprogenitors via various nonviral or viral vectors has been reported, in general, nonviral vectors suffer from poor delivery efficiencies whereas viral vectors (for example adenoviral or retroviral vectors) raise safety concerns (for review, see Gelse and Schneider, 2 Cucchiarini and Madry, 3 Robbins and Ghivizzani, 6 Evans et al 7 ). In marked contrast, baculovirus mediates efficient gene delivery into articular chondrocytes.…”

“…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.…”

“…The genes may be delivered with retrovirus, lentivirus, adenovirus, adeno-associated virus, herpes simplex virus or other nonviral vectors. 3,6,7 Besides the aforementioned vectors, baculovirus, a DNA virus that infects insects as its natural host, has emerged as a novel vector for in vitro and in vivo gene delivery. Despite the expanding applications that include the development of cell-based assays, delivery of small interfering RNA, surface display of eukaryotic proteins, study of gene functions (for review, see Kost et al, 8 Hu 9,10 ) and even delivery of vaccine immunogens 11 or cancer therapy, 12 the applications of baculovirusmediated gene delivery in cartilage repair or tissue engineering are yet to be reported.…”