Delayed administration of adenoviral BMP-2 vector improves the formation of bone in osseous defects

Abstract

The direct, local, administration of adenovirus carrying human BMP-2 cDNA (Ad.BMP-2) heals critical-sized femoral bone defects in rabbit and rat models. However, the outcome is suboptimal and the technology needs to provide a more reliable and uniform outcome. To this end, we investigated whether the timing of Ad.BMP-2 administration influenced the formation of mineralized tissue within the defect. Criticalsized defects were created in the femora of 28 SpragueDawley rats. Animals were injected intralesionally with a single, percutaneous injection of Ad.BMP-2 (4 Â 10 8 plaqueforming units) either intraoperatively (day 0) or 24 h (day 1), 5 days or 10 days after surgery. The femora were evaluated 8 weeks after surgery by X-ray, microcomputed tomography, dual-energy X-ray absorptiometry and biomechanical testing. The incidence of radiological union was markedly increased when administration of Ad.BMP-2 was delayed until days 5 and 10, at which point 86% of the defects healed. These time points also provided greater bone mineral content within the defect site and improved the average mechanical strength of the healed bone. Thus, delaying the injection of Ad.BMP-2 until 5 or 10 days after surgery enables a greater percentage of critical-sized, segmental defects to achieve radiological union, producing a repair tissue with enhanced mineralization and greater mechanical strength.

Enhanced healing of goat femur‐defect using BMP7 gene‐modified BMSCs and load‐bearing tissue‐engineered bone

“…Adenoviral vectors are attractive because both dividing and nondividing cells can be transduced, and there is only short-term production of the gene of BMPs which meet the needs of bone formation. So, a number of laboratories have evaluated the potential of adenoviral BMP-2 to promote spinal fusion in a variety of preclinical models, 27,28 but little research has been done to evaluate the adeno-BMP7 to enhance healing of segmental weight-bearing bone defects. Adeno-BMP7-transduced BMSCs could express BMP7 up to 2-6 weeks, 29,30 inducing the implanted BMSCs and peripheral MSCs to differentiate into osteoblasts, trigger bone regeneration, and repair the defects.…”

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) …”

Progress and Prospects: genetic treatments for disorders of bones and joints

“…Because the biology of a fracture site evolves, Betz et al 32 injected Ad.BMP-2 into an experimental rat segmental defect at different times after surgery. They noted a marked increase in repair when the administration of vector was delayed for 5-10 days.…”