Pre-clinical studies of retrovirally transduced human chondrocytes expressing transforming growth factor-beta-1 (TG-C)

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

“…TG-C was completely cleared from tissues by day 15 and from lung by day 30; in addition, PCR analysis of TG-C DNA performed on blood and other tissues retrieved by rabbits and goats at 30 days and 8 weeks, respectively, did not show any signs [81]. 3 and 6-months safety and efficacy study of TG-C to treat mono-laterally partial cartilage defect (patellar groove) in rabbits highlighted a relationship between intra-articular TG-C administered dose and speed of cartilage regeneration.…”

“…However, no cartilage regeneration was associated with the lowest dose administered (1.8 × 10 6 cells/animal). Eight-week pilot and 1-year safety and efficacy study of TG-C to treat bilaterally single full-thickness cartilage defects (patellar groove) in goats showed in comparison to control group (vehicle) that: (1) hyaline cartilage was present in defects, without relationship to exercise restriction at 8 weeks from TG-C intraarticular administration (1 × 10 6 or 1 × 10 7 cells); and (2) a positive effect on the joint cartilage may be present at 6 months and diminish at 12 months after TG-C intraarticular administration (3 × 10 7 cells) [81].…”

“…For these reasons, retroviruses have been used only for ex vivo gene delivery procedures, adopting the strategy to select cultured cells through a selection marker (i.e. antibiotic resistance) and consequently irradiate them to prevent further in vivo growth and minimize tumour development [70,81]. Finally, the viral vector least employed is baculovirus, a virus that infects insect cells, but that is also able to transduce numerous mammalian cells, including chondrocytes and ADSCs for TGF-β [82] and BMPs [82,83] in vitro and in vivo.…”

“…Preclinical studies of gene therapy for chondral and osteochondral regeneration reported in literature were on safety and efficacy of intra-articular administration of: (a) a 3:1 mixture of normal human chondrocytes and genetically modified human chondrocytes expressing TGF-β1 (TG-C, TissueGene, Inc., Rockville, USA) [81]; (b) a rAAV vector containing the cDNA for a human tumor necrosis factor receptor (TNFR) and immunoglobulin (IgG1) Fc fragment (TNFR:Fc) fusion gene (tgAAC94, Targeted Genetics Corporation, Seattle-Washington, USA) [98]; (c) genetically modified synovial cells (self-complementing recombinant AAV vector delivered in vitro) that express IL-1 Ra (scrAAV2.5IL-1Ra, Mayo Clinic, Rochester, Minnesota, USA). [60,97]; and (d) rAAV vector expressing human interferon-β (ART-I02, Arthrogen, Amsterdam, The Netherlands) [99,100].…”

“…Regarding preclinical evaluation of TG-C, three different studies were carried out to evaluate its biodistribution in SCID mice, and its safety and efficacy in knee articular damage in rabbit and goat models at short, mid and long experimental times [81]. TG-C was completely cleared from tissues by day 15 and from lung by day 30; in addition, PCR analysis of TG-C DNA performed on blood and other tissues retrieved by rabbits and goats at 30 days and 8 weeks, respectively, did not show any signs [81].…”