Direct delayed human adenoviral BMP-2 or BMP-6 gene therapy for bone and cartilage regeneration in a pony osteochondral model

Abstract

Delivery of Ad-BMP-2 or Ad-BMP-6 via direct injection supported cartilage and subchondral bone regeneration but was insufficient to provide long-term quality osteochondral repair.

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

“…Adenovirus is used to transfer GF genes (TGF-β, FGF-2, IGF-1, BMPs and Growth and differentiation factor 5, GDF-5) into cells [8,20,25,[40][41][42][43][44][45][46][47][48][49]. Genes, in encapsuled viral [24] vector, can be injected directly in vivo [50,51] or through decalcified cortical bone matrix (DCBM) as scaffold that contains the viral particles [52]. Indian hedgehog homolog (iHH) and SOXs genes employ adenovirus for transport into MSCs both in vitro [53,54] and in vivo [55,56].…”

“…Direct injection is mainly employed for the delivery of anti-inflammatory cytokines such as IL10 and IL1ra into a joint affected by rheumatoid arthritis, OA and full-thickness defects [12,57,67,68,78]. Even GFs, such as IGF1 and BMPs are delivered with this modality in arthritis, full-thickness and osteochondral defects [50,51,57,63]. In the direct procedures, the most employed vectors are adenovirus, rAAV or scAAV [50, 51, 57, 63, 67, 68], followed by plasmid [12] and Lentivirus [78] (Table 1).…”

“…The cell vehicles, with and without scaffolds, are MSCs of different origin [14, 17, 26, 27, 40-42, 46, 54, 55, 59, 61, 71-75, 77, 82], chondrocytes [16,21,44,59,61,62,70,83] and, to a lesser extent, fibroblasts [18,56]. In fewer cases vectors are implanted into scaffolds without cells as vehicles: the plasmid vector is supported by a collagen I sponge or complexed with bPEI-HA via a porous oligo[poly(ethylene glycol) fumarate] hydrogel scaffold [22,24] and adenoviral vector by DCBM [51] (Table 1).…”

Realizing the potential of gene-based molecular therapies in bone repair

“…Bone induction via endochondral ossification was observed in hindlimb muscle of immunocompetent rats (101,102) Viral particles delivered on hydroxyapatite scaffold to the back muscles of immunocompetent rats led to bone formation (103) Bone formation in thigh muscle after delivery of a tetracycline-sensitive expression system was observed in mice only when a tetracycline analogue was administered (153) Orthotopic AV Increased regeneration in a mandibular distraction osteogenesis model in rats (154) Increased bone regeneration in an osteoporotic fracture model in tibia of sheep (155) Bone formation or increased regeneration was observed in several defect models, including a critical-size mandibular defect, (33) critical-size nasal defect in athymic nude mice, (156) rib defect in horses, (157) metatarsal defect in horses, (158) and femoral critical-size defect in rats (159) Injected AVs led to partial regeneration of critical-size calvarial defects in rats, with a more vigorous response when particles were delivered in a gelatin scaffold (117) Healing of iliac crest critical-size defects in sheep was delayed compared with no treatment when viral particles were injected to injury site (160) Bone formation was observed in a dental model in immunocompetent dogs (107) Enhanced cartilage and subchondral bone was observed in femur condyle defect in immunocompetent ponies (161) Delaying administration of viral particles improved healing of femur critical-size defects in rats (162) …”

“…Ectopic AV Bone formation in quadriceps in athymic nude mice, (35) in thigh muscle of various immunocompetent rat strains, (36,37) and in calf muscle of nude athymic rats (34) Orthotopic AV Enhanced cartilage and subchondral bone formation in a femur condyle defect model in immunocompetent ponies (161) …”